title: CLEC4M and STXBP5 gene variations contribute to von Willebrand factor level variation in von Willebrand disease.
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.
  
  
  OBJECTIVE
  To investigate the association between single-nucleotide polymorphisms (SNPs), VWF levels, and bleeding phenotype.
  
  
  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.
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Y V
authors.initials: YV
authors.lastname: Sanders
authors.affiliation: Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.|Jon J. van Rood Center for Clinical Transfusion Medicine, Sanquin Research, Leiden, The Netherlands.
authors.forename: J G
authors.initials: JG
authors.lastname: van der Bom
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: A
authors.initials: A
authors.lastname: Isaacs
authors.affiliation: Department of Pediatric Hematology, Erasmus University Medical Center/Sophia Children's Hospital, Rotterdam, The Netherlands.
authors.forename: M H
authors.initials: MH
authors.lastname: Cnossen
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: M P M
authors.initials: MP
authors.lastname: de Maat
authors.affiliation: Department of Hematology, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: B A P
authors.initials: BA
authors.lastname: Laros-van Gorkom
authors.affiliation: Department of Pediatric Hematology, Emma Children's Hospital, Academic Medical Center, Amsterdam, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Fijnvandraat
authors.affiliation: Department of Hematology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
authors.forename: K
authors.initials: K
authors.lastname: Meijer
authors.affiliation: Genetic Epidemiology Unit, Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: C M
authors.initials: CM
authors.lastname: van Duijn
authors.affiliation: van Creveldkliniek/Department of Hematology, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: E P
authors.initials: EP
authors.lastname: Mauser-Bunschoten
authors.affiliation: Department of Thrombosis and Hemostasis, Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Eikenboom
authors.affiliation: Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: F W G
authors.initials: FW
authors.lastname: Leebeek
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015415:Biomarkers / Q000097:blood; D001777:Blood Coagulation / Q000235:genetics*; D001780:Blood Coagulation Tests; D015815:Cell Adhesion Molecules / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D003430:Cross-Sectional Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006470:Hemorrhage / Q000097:blood / Q000235:genetics; D006801:Humans; D007223:Infant; D037181:Lectins, C-Type / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D025202:Molecular Diagnostic Techniques; D009419:Nerve Tissue Proteins / Q000235:genetics*; D009426:Netherlands; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D050683:R-SNARE Proteins / Q000235:genetics*; D011956:Receptors, Cell Surface / Q000235:genetics*; D012307:Risk Factors; D055815:Young Adult; D056725:von Willebrand Disease, Type 1 / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D056728:von Willebrand Disease, Type 2 / Q000097:blood / Q000175:diagnosis / Q000235:genetics*; D014841:von Willebrand Factor / Q000032:analysis*
chemical_list: D015415:Biomarkers; C433029:CLEC4M protein, human; D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D009419:Nerve Tissue Proteins; D050683:R-SNARE Proteins; D011956:Receptors, Cell Surface; C484767:STXBP5 protein, human; D014841:von Willebrand Factor
keywords: CLEC4M protein, human; STXBP5 protein, human; polymorphism, single nucleotide; von Willebrand disease; von Willebrand factor