Abstract
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, e.g. VWF, ABO, STXBP5 and CLEC4M. This study aims to screen comprehensively for CLEC4M variants and investigate their association with type 1 VWD in the Swedish population. In order to screen for CLEC4M variants, the CLEC4M gene region was re-sequenced and the polymorphic neck region was genotyped in 106 type 1 VWD patients from unrelated type 1 VWD families. Single nucleotide variants (SNV) and variable number tandem repeat (VNTR) allele and genotype frequencies were then compared with 294 individuals from the 1000Genomes project and 436 Swedish control individuals. Re-sequencing identified a total of 42 SNVs. Rare variants showed no accumulation in type 1 VWD patients and are not thought to contribute substantially to type 1 VWD. The only missense mutation (rs2277998, NP_001138379.1:p.Asp224Asn) had a higher frequency in type 1 VWD patients than in controls (4.9%). The VNTR genotypes 57 and 67 were observed at higher frequencies than expected in type 1 VWD patients (6.4% and 6.2%) and showed an increase in patients compared with controls (7.4% and 3.1%). Strong linkage disequilibrium in the CLEC4M region makes it difficult to distinguish between the effect of the missense mutation and the VNTR genotypes. In conclusion, heterozygous VNTR genotypes 57 and 67 of CLEC4M were highly enriched and are the most likely mechanism through which CLEC4M contributes to disease in the Swedish type 1 VWD population.
Highlights
Introduction von Willebrand disease (VWD) is characterized by low levels of, or defective plasma von Willebrand factor (VWF) and is classified into three different types depending on the nature of the disease
Not all index cases fulfilled the modern definition of type 1 VWD, but at the time of diagnosis their bleeding symptoms in combination with lowered VWF levels were interpreted as reflecting type 1 VWD
Since the present study investigated one of the additional factors associated with VWF level variation, individuals with bleeding symptoms and low VWF levels were included in the study regardless of whether they had bona fide VWF mutations or not
Summary
Introduction vonWillebrand disease (VWD) is characterized by low levels of, or defective plasma von Willebrand factor (VWF) and is classified into three different types depending on the nature of the disease. Type 1 VWD is the least serious subtype accounting for approximately 70% of diagnosed cases and is defined as a partial deficiency of functionally normal VWF. In most cases it shows dominant inheritance [1]. Even in well-defined type 1 VWD patient groups approximately 35% of all type 1 VWD patients do not have a mutation in the promoter, coding sequence or splice junctions of the VWF gene [1]. This suggests that other genes affect the level.
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