Common VWF exon 28 polymorphisms in African Americans affecting the VWF activity assay by ristocetin cofactor.
The diagnosis of von Willebrand disease relies on abnormalities in specific tests of von Willebrand factor (VWF), including VWF antigen (VWF:Ag) and VWF ristocetin cofactor activity (VWF:RCo). When examining healthy controls enrolled in the T. S. Zimmerman Program for the Molecular and Clinical Biology of von Willebrand disease, we, like others, found a lower mean VWF:RCo compared with VWF:Ag in African American controls and therefore sought a genetic cause for these differences. For the African American controls, the presence of 3 exon 28 single nucleotide polymorphisms (SNPs), I1380V, N1435S, and D1472H, was associated with a significantly lower VWF:RCo/VWF:Ag ratio, whereas the presence of D1472H alone was associated with a decreased ratio in both African American and Caucasian controls. Multivariate analysis comparing race, SNP status, and VWF:RCo/VWF:Ag ratio confirmed that only the presence of D1472H was significant. No difference was seen in VWF binding to collagen, regardless of SNP status. Similarly, no difference in activity was seen using a GPIb complex-binding assay that is independent of ristocetin. Because the VWF:RCo assay depends on ristocetin binding to VWF, mutations (and polymorphisms) in VWF may affect the measurement of "VWF activity" by this assay and may not reflect a functional defect or true hemorrhagic risk.
Flood
Veronica H
VH
Department of Pediatrics, Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI 53201, USA. vflood@mcw.edu
Gill
Joan Cox
JC
Morateck
Patricia A
PA
Christopherson
Pamela A
PA
Friedman
Kenneth D
KD
Haberichter
Sandra L
SL
Branchford
Brian R
BR
Hoffmann
Raymond G
RG
Abshire
Thomas C
TC
Di Paola
Jorge A
JA
Hoots
W Keith
WK
Leissinger
Cindy
C
Lusher
Jeanne M
JM
Ragni
Margaret V
MV
Shapiro
Amy D
AD
Montgomery
Robert R
RR
D001741:Black or African American / Q000235:genetics; D003435:Crotalid Venoms; D005091:Exons; D006801:Humans; D010979:Platelet Function Tests / Q000379:methods*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D012310:Ristocetin / Q000378:metabolism; D014842:von Willebrand Diseases / Q000175:diagnosis* / Q000235:genetics / Q000378:metabolism; D014841:von Willebrand Factor / Q000032:analysis* / Q000235:genetics* / Q000378:metabolism
D003435:Crotalid Venoms; D014841:von Willebrand Factor; D012310:Ristocetin; C030961:botrocetin