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. 2012;7(7):e40624.
doi: 10.1371/journal.pone.0040624. Epub 2012 Jul 6.

Effect of genetic variation in STXBP5 and STX2 on von Willebrand factor and bleeding phenotype in type 1 von Willebrand disease patients

Janine E van Loon  1 , Yvonne V Sanders, Eva M de Wee, Marieke J H A Kruip, Moniek P M de Maat, Frank W G Leebeek
Affiliations

Effect of genetic variation in STXBP5 and STX2 on von Willebrand factor and bleeding phenotype in type 1 von Willebrand disease patients

Janine E van Loon et al. PLoS One. 2012.

Abstract

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.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Haplotype analysis for rs1039084 and rs9399599.
Graph presents the coefficients with standard error per haplotype. Haplotype 1 was used as reference haplotype. NS = not significant.
Figure 2
Figure 2. Bleeding score.
Bleeding score per genotype for each SNP for the total group and stratified by sex. * P<0.05.
See this image and copyright information in PMC

References

    1. Ruggeri ZM. Old concepts and new developments in the study of platelet aggregation. J Clin Invest. 2000;105:699–701. - PMC - PubMed
    1. Ruggeri ZM, Ware J. von Willebrand factor. Faseb J. 1993;7:308–316. - PubMed
    1. Sadler JE, Budde U, Eikenboom JC, Favaloro EJ, Hill FG, et al. Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand Factor. J Thromb Haemost. 2006;4:2103–2114. - PubMed
    1. Smith NL, Chen MH, Dehghan A, Strachan DP, Basu S, et al. Novel associations of multiple genetic loci with plasma levels of factor VII, factor VIII, and von Willebrand factor: The CHARGE (Cohorts for Heart and Aging Research in Genome Epidemiology) Consortium. Circulation. 2010;121:1382–1392. - PMC - PubMed
    1. Widberg CH, Bryant NJ, Girotti M, Rea S, James DE. Tomosyn interacts with the t-SNAREs syntaxin4 and SNAP23 and plays a role in insulin-stimulated GLUT4 translocation. J Biol Chem. 2003;278:35093–35101. - PubMed

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