Genetic Variation in the von Willebrand Factor Gene in Swedish von Willebrand Disease Patients

Abstract

Abstractvon Willebrand factor (VWF) level and function are influenced by genetic variation in VWF and several other genes in von Willebrand disease type 1 (VWD1) patients. This study comprehensively screened for VWF variants and investigated the presence of ABO genotypes and common and rare VWF variants in Swedish VWD1 patients. The VWF gene was resequenced using Ion Torrent and Sanger sequencing in 126 index cases historically diagnosed with VWD. Exon 7 of the ABO gene was resequenced using Sanger sequencing. Multiplex ligation-dependent probe amplification analysis was used to investigate for copy number variants. Genotyping of 98 single nucleotide variants allowed allele frequency comparisons with public databases. Seven VWD2 mutations and 36 candidate VWD1 mutations (5 deletions, 4 nonsense, 21 missense, 1 splice, and 5 synonymous mutations) were identified. Nine mutations were found in more than one family and nine VWD1 index cases carried more than one candidate mutation. The T-allele of rs1063857 (c.2385T > C, p.Y795 = ) and blood group O were both frequent findings and contributed to disease in the Swedish VWD1 population. VWD2 mutations were found in 20 and candidate VWD1 mutations in 51 index cases out of 106 (48%). VWF mutations, a VWF haplotype, and blood group O all contributed to explain disease in Swedish VWD1 patients.

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

“…Thus, the historic type 1 VWD population is very similar to our type 1 VWD population where 48% of the patients had rare VWF variants and 70% had blood group O. 17 There are clear differences between VWD populations defined using historic and contemporary definitions. For example, Sanders et al 7 compared the A-allele frequency of rs9390459 in their type 1 VWD population (0.47) with that of healthy individuals in the CHARGE study (0.44).…”

“…The 127 unrelated patients have been characterized with respect to their VWF mutations. 17 Previous deoxyribonucleic acid (DNA) sequencing have identified mutations in 20 type 2 VWD patients among the 127 patients initially diagnosed with type 1 VWD. The remaining 107 type 1 VWD patients (76 females and 31 males) have been analysed in this study.…”

Common and Rare Variants in Genes Associated with von Willebrand Factor Level Variation: No Accumulation of Rare Variants in Swedish von Willebrand Disease Patients

“…The sequencing detected a total of 146 variants in the coding sequences of the eight genes. Excluding 70 variants in VWF (described in detail in the study by Manderstedt et al), 8 76 variants remained. There were a total of 19 variants in ABO : eight missense, two frameshift, and nine synonymous.…”

“…VWF harbored 70 of these, of which many were mutations and have been described in detail previously. 8 Of the remaining 76 variants, 54 had allele frequencies > 0.5% and a majority of these have therefore likely already been investigated for their association with the VWF level in later GWAS also investigating low-frequency variants in these and other genes. 4 6 The rs141041254 STAB2 variant associated with VWF level variation and identified by Huffman et al 4 was not found in this study, but it has been further investigated along with common variants in STAB2 .…”

“…Previous DNA sequencing identified type 2 VWD mutations in 20 patients among the 127 patients initially diagnosed with VWD. 8 Of the remaining 107 VWD patients, 104 were analyzed in this study. Of the 104 patients, 72 had a family history of bleeding in addition to their bleeding phenotypes.…”