Common and rare von Willebrand factor (VWF) coding variants, VWF levels, and factor VIII levels in African Americans: the NHLBI Exome Sequencing Project

• Published in: Blood Vol. 122; no. 4; pp. 590 - 597
• Main Authors: Johnsen, Jill M., Auer, Paul L., Morrison, Alanna C., Jiao, Shuo, Wei, Peng, Haessler, Jeffrey, Fox, Keolu, McGee, Sean R., Smith, Joshua D., Carlson, Christopher S., Smith, Nicholas, Boerwinkle, Eric, Kooperberg, Charles, Nickerson, Deborah A., Rich, Stephen S., Green, David, Peters, Ulrike, Cushman, Mary, Reiner, Alex P.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.07.2013; American Society of Hematology
• Subjects: Adult; African Americans - genetics; African Americans - statistics & numerical data; Aged; Blood Chemical Analysis; Cohort Studies; Exome - genetics; Factor VIII - analysis; Female; Gene Frequency; High-Throughput Nucleotide Sequencing; Humans; Male; Middle Aged; Mutation, Missense - physiology; National Heart, Lung, and Blood Institute (U.S.); Open Reading Frames - genetics; Polymorphism, Single Nucleotide - physiology; Thrombosis and Hemostasis; United States; von Willebrand Factor - analysis; von Willebrand Factor - genetics; Young Adult; United States
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2013-02-485094

Several rare European von Willebrand disease missense variants of VWF (including p.Arg2185Gln and p.His817Gln) were recently reported to be common in apparently healthy African Americans (AAs). Using data from the NHLBI Exome Sequencing Project, we assessed the association of these and other VWF coding variants with von Willebrand factor (VWF) and factor VIII (FVIII) levels in 4468 AAs. Of 30 nonsynonymous VWF variants, 6 were significantly and independently associated (P < .001) with levels of VWF and/or FVIII. Each additional copy of the common VWF variants encoding p.Thr789Ala or p.Asp1472His was associated with 6 to 8 IU/dL higher VWF levels. The VWF variant encoding p.Arg2185Gln was associated with 7 to 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. A novel, rare missense VWF variant that predicts disruption of an O-glycosylation site (p.Ser1486Leu) and a rare variant encoding p.Arg2287Trp were each associated with 30 to 40 IU/dL lower VWF level (P < .001). In summary, several common and rare VWF missense variants contribute to phenotypic differences in VWF and FVIII among AAs. •Several common and rare VWF missense variants contribute to phenotypic differences in VWF and FVIII among African Americans.•Next-generation sequencing technology and improved genotype imputation can contribute to molecular genetics of VWD-related phenotypes.