title: VWF mutations and new sequence variations identified in healthy controls are more frequent in the African-American population.
abstract: Diagnosis and classification of VWD is aided by molecular analysis of the VWF gene. Because VWF polymorphisms have not been fully characterized, we performed VWF laboratory testing and gene sequencing of 184 healthy controls with a negative bleeding history. The controls included 66 (35.9%) African Americans (AAs). We identified 21 new sequence variations, 13 (62%) of which occurred exclusively in AAs and 2 (G967D, T2666M) that were found in 10%-15% of the AA samples, suggesting they are polymorphisms. We identified 14 sequence variations reported previously as VWF mutations, the majority of which were type 1 mutations. These controls had VWF Ag levels within the normal range, suggesting that these sequence variations might not always reduce plasma VWF levels. Eleven mutations were found in AAs, and the frequency of M740I, H817Q, and R2185Q was 15%-18%. Ten AA controls had the 2N mutation H817Q; 1 was homozygous. The average factor VIII level in this group was 99 IU/dL, suggesting that this variation may confer little or no clinical symptoms. This study emphasizes the importance of sequencing healthy controls to understand ethnic-specific sequence variations so that asymptomatic sequence variations are not misidentified as mutations in other ethnic or racial groups.
authors.affiliation: Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI, USA. dan.bellissimo@bcw.edu
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Bellissimo
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Christopherson
authors.forename: Veronica H
authors.initials: VH
authors.lastname: Flood
authors.forename: Joan Cox
authors.initials: JC
authors.lastname: Gill
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Friedman
authors.forename: Sandra L
authors.initials: SL
authors.lastname: Haberichter
authors.forename: Amy D
authors.initials: AD
authors.lastname: Shapiro
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Abshire
authors.forename: Cindy
authors.initials: C
authors.lastname: Leissinger
authors.forename: W Keith
authors.initials: WK
authors.lastname: Hoots
authors.forename: Jeanne M
authors.initials: JM
authors.lastname: Lusher
authors.forename: Margaret V
authors.initials: MV
authors.lastname: Ragni
authors.forename: Robert R
authors.initials: RR
authors.lastname: Montgomery
mesh_terms: D001741:Black or African American / Q000235:genetics*; D019943:Amino Acid Substitution; D005091:Exons; D023061:Gene Order; D014644:Genetic Variation; D006801:Humans; D009154:Mutation; D014842:von Willebrand Diseases / Q000208:ethnology* / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics* / Q000378:metabolism
chemical_list: D014841:von Willebrand Factor