Common and rare von Willebrand factor (VWF) coding variants, von Willebrand factor levels, and factor VIII levels in African Americans.

Publication Type:

Journal Article


Blood, Volume 122, Issue 4, p.590-7 (2013)


2013, Center-Authored Paper, June 2013, Public Health Sciences Division, Specimen Processing Core Facility


Several rare European type 1 and 2N von Willebrand disease missense variants of VWF (including p.Arg2185Gln and p.His817Gln) were recently reported to be common [minor allele frequency (MAF) 10-15%] in apparently healthy African Americans (AA). Using data from the NHLBI Exome Sequencing Project, we assessed the association of these and other common and low frequency VWF coding variants with von Willebrand factor (VWF) and factor VIII (FVIII) levels in a population-based sample of 4,468 AA. Of 30 non-synonymous VWF variants, 6 were significantly and independently associated (P<0.001) with levels of VWF and/or FVIII. Each additional copy of the VWF variants encoding the common p.Thr789Ala or p.Asp1472His amino acid substitutions was associated with 6-8 IU/dL higher VWF levels. The VWF variant encoding p.Arg2185Gln was associated with 7-13 IU/dL lower VWF and FVIII levels. The type 2N-related VWF variant encoding p.His817Gln was associated with 17 IU/dL lower FVIII level but normal VWF level (P=0.57). A novel, rare (MAF=0.8%) missense VWF variant that predicts disruption of an O-glycosylation site (p.Ser1486Leu) and a rare (MAF = 0.7%) variant encoding p.Arg2287Trp were each associated with 30-40 IU/dL lower VWF level (P<0.001). In summary several common and rare VWF missense variants contribute to phenotypic differences in VWF and FVIII among AA.