Effect of genetic variation in STXBP5 and STX2 on von Willebrand factor and bleeding phenotype in type 1 von Willebrand disease patients.
BACKGROUND
In type 1 von Willebrand Disease (VWD) patients, von Willebrand Factor (VWF) levels and bleeding symptoms are highly variable. Recently, the association between genetic variations in STXBP5 and STX2 with VWF levels has been discovered in the general population. We assessed the relationship between genetic variations in STXBP5 and STX2, VWF levels, and bleeding phenotype in type 1 VWD patients.


METHODS
In 158 patients diagnosed with type 1 VWD according to the current ISTH guidelines, we genotyped three tagging-SNPs in STXBP5 and STX2 and analyzed their relationship with VWF:Ag levels and the severity of the bleeding phenotype, as assessed by the Tosetto bleeding score.


RESULTS
In STX2, rs7978987 was significantly associated with VWF:Ag levels (bèta-coefficient (β) = -0.04 IU/mL per allele, [95%CI -0.07;-0.001], p = 0.04) and VWF:CB activity (β = -0.12 IU/mL per allele, [95%CI -0.17;-0.06], p<0.0001). For rs1039084 in STXBP5 a similar trend with VWF:Ag levels was observed: (β = -0.03 IU/mL per allele [95% CI -0.06;0.003], p = 0.07). In women, homozygous carriers of the minor alleles of both SNPs in STXBP5 had a significantly higher bleeding score than homozygous carriers of the major alleles. (Rs1039084 p = 0.01 and rs9399599 p = 0.02).


CONCLUSIONS
Genetic variation in STX2 is associated with VWF:Ag levels in patients diagnosed with type 1 VWD. In addition, genetic variation in STXBP5 is associated with bleeding phenotype in female VWD patients. Our findings may partly explain the variable VWF levels and bleeding phenotype in type 1 VWD patients.
Department of Haematology, Erasmus Medical Center, Rotterdam, The Netherlands.
Janine E
JE
van Loon
Yvonne V
YV
Sanders
Eva M
EM
de Wee
Marieke J H A
MJ
Kruip
Moniek P M
MP
de Maat
Frank W G
FW
Leebeek
D000328:Adult; D005260:Female; D006239:Haplotypes; D006470:Hemorrhage / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D050683:R-SNARE Proteins / Q000235:genetics*; D050827:Syntaxin 1 / Q000235:genetics*; D055815:Young Adult; D056725:von Willebrand Disease, Type 1 / Q000235:genetics* / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D050683:R-SNARE Proteins; C074558:STX2 protein, human; C484767:STXBP5 protein, human; D050827:Syntaxin 1; D014841:von Willebrand Factor