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Lind-Halldén, C., Manderstedt, E., Carlberg, D., Lethagen, S. & Halldén, C. (2018). Genetic variation in the syntaxin-binding protein STXBP5 in type 1 von Willebrand disease patients. Thrombosis and haemostasis, 118(8), 1382-1389
Open this publication in new window or tab >>Genetic variation in the syntaxin-binding protein STXBP5 in type 1 von Willebrand disease patients
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2018 (English)In: Thrombosis and haemostasis, ISSN 2567-689X, Vol. 118, no 8, p. 1382-1389Article in journal (Refereed) Published
Abstract [en]

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.

von Willebrand disease - VWD - re-sequence - STXBP5 - mutation
National Category
Other Medical Sciences Biomedical Laboratory Science/Technology
urn:nbn:se:hkr:diva-18368 (URN)10.1055/s-0038-1661352 (DOI)000440219100007 ()29972863 (PubMedID)
Available from: 2018-07-10 Created: 2018-07-10 Last updated: 2019-01-11Bibliographically approved
Henmyr, V., Lind-Halldén, C., Halldén, C., Säll, T., Carlberg, D., Bachert, C. & Cardell, L.-O. (2016). Chronic rhinosinusitis patients show accumulation of genetic variants in PARS2. PLoS ONE, 11(6), Article ID e0158202.
Open this publication in new window or tab >>Chronic rhinosinusitis patients show accumulation of genetic variants in PARS2
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2016 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 6, article id e0158202Article in journal (Refereed) Published
Abstract [en]

Genetic studies of chronic rhinosinusitis (CRS) have identified a total of 53 CRS-associated SNPs that were subsequently evaluated for their reproducibility in a recent study. The rs2873551 SNP in linkage disequilibrium with PARS2 showed the strongest association signal. The present study aims to comprehensively screen for rare variants in PARS2 and evaluate for accumulation of such variants in CRS-patients. Sanger sequencing and long-range PCR were used to screen for rare variants in the putative promoter region and coding sequence of 310 CRS-patients and a total of 21 variants were detected. The mutation spectrum was then compared with data from European populations of the 1000Genomes project (EUR) and the Exome Aggregation Consortium (ExAC). The CRS population showed a significant surplus of low-frequency variants compared with ExAC data. Haplotype analysis of the region showed a significant excess of rare haplotypes in the CRS population compared to the EUR population. Two missense mutations were also genotyped in the 310 CRS patients and 372 CRS-negative controls, but no associations with the disease were found. This is the first re-sequencing study in CRS research and also the first study to show an association of rare variants with the disease.

National Category
Medical and Health Sciences
urn:nbn:se:hkr:diva-16091 (URN)10.1371/journal.pone.0158202 (DOI)000378801200050 ()27348859 (PubMedID)
Available from: 2016-09-28 Created: 2016-09-28 Last updated: 2017-11-21Bibliographically approved

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