Department of Haematology, Erasmus Medical Center, Rotterdam, The Netherlands.
PLoS One. 2012;7(7):e40624. doi: 10.1371/journal.pone.0040624. Epub 2012 Jul 6.
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.
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.
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).
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.
在 1 型血管性血友病（VWD）患者中，血管性血友病因子（VWF）水平和出血症状存在高度变异性。最近，在普通人群中发现了 STXBP5 和 STX2 中的遗传变异与 VWF 水平之间的关联。我们评估了 158 例根据当前 ISTH 指南诊断为 1 型 VWD 的患者中 STXBP5 和 STX2 中的遗传变异与 VWF 水平和出血表型之间的关系，出血表型的严重程度通过 Tosetto 出血评分进行评估。
在 158 例根据当前 ISTH 指南诊断为 1 型 VWD 的患者中，我们对 STXBP5 和 STX2 中的三个标记 SNP 进行基因分型，并分析它们与 VWF:Ag 水平和出血表型严重程度之间的关系，出血表型的严重程度通过 Tosetto 出血评分进行评估。
在 STX2 中，rs7978987 与 VWF:Ag 水平显著相关（β系数（β）=-0.04 IU/mL 每等位基因，[95%CI -0.07;-0.001]，p=0.04）和 VWF:CB 活性（β=-0.12 IU/mL 每等位基因，[95%CI -0.17;-0.06]，p<0.0001）。对于 STXBP5 中的 rs1039084，也观察到与 VWF:Ag 水平相似的趋势：（β=-0.03 IU/mL 每等位基因[95%CI -0.06;0.003]，p=0.07）。在女性中，这两个 SNP 的 minor 等位基因纯合携带者的出血评分明显高于 major 等位基因纯合携带者。（rs1039084 p=0.01，rs9399599 p=0.02）。
STX2 中的遗传变异与诊断为 1 型 VWD 的患者的 VWF:Ag 水平相关。此外，STXBP5 中的遗传变异与女性 VWD 患者的出血表型相关。我们的发现可能部分解释了 1 型 VWD 患者中 VWF 水平和出血表型的变异性。
