Y V Sanders1, J G van der Bom2,3, A Isaacs4, M H Cnossen5, M P M de Maat1, B A P Laros-van Gorkom6, K Fijnvandraat7, K Meijer8, C M van Duijn4, E P Mauser-Bunschoten9, J Eikenboom10, F W G Leebeek1. 1. Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands. 2. Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands. 3. Jon J. van Rood Center for Clinical Transfusion Medicine, Sanquin Research, Leiden, The Netherlands. 4. Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands. 5. Department of Pediatric Hematology, Erasmus University Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands. 6. Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands. 7. Department of Pediatric Hematology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands. 8. Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 9. van Creveldkliniek/Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands. 10. Department of Thrombosis and Hemostasis, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Abstract
BACKGROUND: von Willebrand factor (VWF) levels in healthy individuals are influenced by variations in genetic loci other than the VWF gene, whose contribution to VWF levels in patients with von Willebrand disease (VWD) is largely unknown. OBJECTIVES: To investigate the association between single-nucleotide polymorphisms (SNPs), VWF levels, and bleeding phenotype. PATIENTS/ METHODS: In 364 type 1 VWD and 240 type 2 VWD patients from the nationwide cross-sectional 'Willebrand in The Netherlands' (WiN) study, we studied the association between eight SNPs in STXBP5, SCARA5, ABO, VWF, STAB2, STX2, TC2N, and CLEC4M, and VWF antigen (VWF:Ag), VWF activity (VWF:Act), and bleeding phenotype as assessed with the Tosetto bleeding score. RESULTS: In type 1 patients, STXBP5 was associated with a lower VWF:Ag level (adjusted difference of -3.0 IU dL(-1) per allele; 95% confidence interval [CI] -6.0 to 0.1) and CLEC4M with both a lower VWF:Ag level (-4.3 IU dL(-1) per allele; 95% CI -7.9 to -0.6) and lower VWF:Act (-5.7 IU dL(-1) per allele; 95% CI -10.9 to -0.5). In type 2 patients, none of the SNPs was associated with VWF levels. None of the genetic variants was associated with bleeding score. CONCLUSIONS: Genetic variations in STXBP5 and CLEC4M are associated with VWF level variation in type 1 VWD, but not in type 2 VWD. This study increases our understanding of the pathophysiology of VWD, and provides a further indication of the involvement of STXBP5 and CLEC4M in determining VWF levels in VWD.
BACKGROUND:von Willebrand factor (VWF) levels in healthy individuals are influenced by variations in genetic loci other than the VWF gene, whose contribution to VWF levels in patients with von Willebrand disease (VWD) is largely unknown. OBJECTIVES: To investigate the association between single-nucleotide polymorphisms (SNPs), VWF levels, and bleeding phenotype. PATIENTS/ METHODS: In 364 type 1 VWD and 240 type 2 VWDpatients from the nationwide cross-sectional 'Willebrand in The Netherlands' (WiN) study, we studied the association between eight SNPs in STXBP5, SCARA5, ABO, VWF, STAB2, STX2, TC2N, and CLEC4M, and VWF antigen (VWF:Ag), VWF activity (VWF:Act), and bleeding phenotype as assessed with the Tosetto bleeding score. RESULTS: In type 1 patients, STXBP5 was associated with a lower VWF:Ag level (adjusted difference of -3.0 IU dL(-1) per allele; 95% confidence interval [CI] -6.0 to 0.1) and CLEC4M with both a lower VWF:Ag level (-4.3 IU dL(-1) per allele; 95% CI -7.9 to -0.6) and lower VWF:Act (-5.7 IU dL(-1) per allele; 95% CI -10.9 to -0.5). In type 2 patients, none of the SNPs was associated with VWF levels. None of the genetic variants was associated with bleeding score. CONCLUSIONS: Genetic variations in STXBP5 and CLEC4M are associated with VWF level variation in type 1 VWD, but not in type 2 VWD. This study increases our understanding of the pathophysiology of VWD, and provides a further indication of the involvement of STXBP5 and CLEC4M in determining VWF levels in VWD.
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