Common VWF sequence variants associated with higher VWF and FVIII are less frequent in subjects diagnosed with type 1 VWD

Unlabelled Box •Specific sequence variants in the VWF D′D3 region are associated with elevated VWF antigen levels. •VWF levels and variant frequencies were examined in both European and Caucasian Americans. •Subjects homozygous for D′D3 variants had the highest VWF and factor VIII levels. •D′D3 variants are less frequent in type 1 VWD, suggesting a potential protective effect. The authors would like to acknowledge funding from the National Institutes of Health (HL081588, HL102260, and HL126810). Additional support was provided by the MACC Fund (Midwest Athletes Against Childhood Cancer) and the BloodCenter Research Fund. The authors would also like to acknowledge the patients, nurses, and research coordinators who make the Zimmerman Program a success. National Institutes of HealthHL081588HL102260HL126810 BloodCenter Research Fund MACC Fund Background Genetic variation in the VWF gene is associated with von Willebrand factor (VWF) and factor VIII (FVIII) levels in healthy individuals. Objectives We hypothesized that VWF sequence variants associated with higher VWF or FVIII could impact the diagnosis of type 1 von Willebrand disease (VWD). Methods We examined VWF antigen (VWF:Ag), VWF ristocetin cofactor activity (VWF:RCo), VWF propeptide (VWFpp), and FVIII levels along with VWF gene sequencing in 256 healthy control and 97 type 1 VWD subjects as part of a cross‐sectional study. Results We found several VWF sequence variants ( VWF c.2880G>A and VWF c.2365A>G(;)c.2385T>C, found in linkage disequilibrium) associated with higher VWF and FVIII levels in healthy controls ( P <.001 for both variants). In addition, these variants were significantly more common in controls than in subjects diagnosed with type 1 VWD and VWF:Ag <30 ( P <.005). The decreased variant frequencies in type 1 VWD was not seen in other VWD types. VWF:Ag, VWF:RCo, and FVIII were not statistically different in type 1 VWD subjects who had these VWF variants compared to type 1 VWD patients without them. There was no difference in ABO blood group, VWF propeptide levels (excluding subjects with known VWF clearance defects), or bleeding score using the ISTH bleeding assessment tool. Conclusions These data suggest that certain VWF sequence variants associated with elevated FVIII and VWF levels may protect against reduced VWF levels. These findings were independent of other pathogenic sequence variants in VWF , suggesting a possible independent effect of c.2880G>A and c.2365A>G(;)c.2385T>C on VWF levels.