Genetic Variation in the Syntaxin-Binding Protein STXBP5 in Type 1 von Willebrand Disease Patients.

Autor:	Lind-Halldén C; Department of Environmental Science and Bioscience, Kristianstad University, Kristianstad, Sweden., Manderstedt E; Department of Environmental Science and Bioscience, Kristianstad University, Kristianstad, Sweden., Carlberg D; Department of Environmental Science and Bioscience, Kristianstad University, Kristianstad, Sweden., Lethagen S; Department for Coagulation Disorders, Skåne University Hospital in Malmö, Malmö, Sweden.; National Haemophilia Center, University Hospital Rigshospitalet, Copenhagen, Denmark.; Sobi, Stockholm, Sweden., Halldén C; Department of Environmental Science and Bioscience, Kristianstad University, Kristianstad, Sweden.
Jazyk:	angličtina
Zdroj:	Thrombosis and haemostasis [Thromb Haemost] 2018 Aug; Vol. 118 (8), pp. 1382-1389. Date of Electronic Publication: 2018 Jul 04.
DOI:	10.1055/s-0038-1661352
Abstrakt:	von Willebrand factor (VWF) levels in healthy individuals and in patients with type 1 von Willebrand disease (VWD) are influenced by genetic variation in several genes, for example, VWF , ABO and STXBP5 . Here, we comprehensively screen for STXBP5 variants and investigate their association with type 1 VWD in Swedish patients and controls. The coding region of the STXBP5 gene was re-sequenced in 107 type 1 VWD patients and the detected variants were genotyped in the type 1 VWD population and a Swedish control population (464 individuals). The functional effects of missense alleles were predicted in silico and the pattern of genetic variation in STXBP5 was analysed. Re-sequencing of 107 type 1 VWD patients identified three missense and three synonymous variants in the coding sequence of STXBP5 . The low-frequency missense variants rs144099092 (0.005) and rs148830578 (0.029) were predicted to be damaging, but were not accumulated in patients. No other rare candidate mutations were detected. STXBP5 showed a high level of linkage disequilibrium and a low overall nucleotide diversity of π  = 3.2 × 10 -4 indicating intolerance to variants affecting protein function. Three previously type 1 VWD-associated single nucleotide polymorphisms were located on one haplotype that showed an increased frequency in patients versus controls. No differences in messenger ribonucleic acid abundance among haplotypes could be found using Genotype-Tissue Expression project data. In conclusion, a haplotype containing the STXBP5 Asn436Ser (rs1039084) mutation is associated with type 1 VWD and no rare STXBP5 mutations contribute to type 1 VWD in the Swedish population. Competing Interests: Stefan Lethagen is employed by and receives salary from Sobi. The funder provided support in the form of salary for the author, but did not have any additional role in the study design, data collection and analysis, decision to publish or preparation of the manuscript. All other authors declare no conflict of interest. (Georg Thieme Verlag KG Stuttgart · New York.)
Databáze:	MEDLINE
Externí odkaz:	Zobrazit plný text záznamu