title: An association of candidate gene haplotypes and bleeding severity in von Willebrand disease (VWD) type 1 pedigrees.
abstract: von Willebrand disease (VWD) type 1 is difficult to diagnose because of bleeding variability and low heritability of von Willebrand factor (VWF) levels. We compared a bleeding severity score and bleeding times to candidate gene haplotypes within pedigrees of 14 index cases, using a covariance components model for multivariate traits (Mendel: QTL Association). These pedigrees included 13 affected and 40 unaffected relatives, as defined by plasma ristocetin cofactor (VWF:RCo) levels. The bleeding severity score was derived from a detailed history. Donors were genotyped using a primer extension method, and 9 candidate genes were selected for analysis. VWF:RCo levels had the strongest influence on bleeding severity score and bleeding time. ITGA2 haplotype 2 (807C) and ITGA2B haplotype 1 (Ile(843)) were each associated with increased bleeding severity scores (P < .01 and P < .01, respectively). GP6 haplotype b (Pro(219)) was also associated with increased scores (P = .03) after adjustment for donor age. No association was observed with 6 other candidate genes, GP1BA, ITGB3, VWF, FGB, IL6, or TXA2R. Increased plasma VWF:Ag levels were associated with VWF haplotype 1 (-1793G; P = .02). These results establish that genetic differences in the adhesion receptor subunits alpha(2), alpha(IIb,) and GPVI can influence the phenotype of VWD type 1.
authors.affiliation: Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 N Torrey Pines Rd, MEM-150, La Jolla, CA 92037, USA. tomk@scripps.edu
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Kunicki
authors.forename: Augusto B
authors.initials: AB
authors.lastname: Federici
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Salomon
authors.forename: James A
authors.initials: JA
authors.lastname: Koziol
authors.forename: Steven R
authors.initials: SR
authors.lastname: Head
authors.forename: Tony S
authors.initials: TS
authors.lastname: Mondala
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Chismar
authors.forename: Luciano
authors.initials: L
authors.lastname: Baronciani
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Canciani
authors.forename: Ian R
authors.initials: IR
authors.lastname: Peake
mesh_terms: D001760:Bleeding Time; D005260:Female; D006023:Glycoproteins / Q000235:genetics; D006239:Haplotypes / Q000235:genetics*; D006470:Hemorrhage / Q000503:physiopathology*; D006801:Humans; D016013:Likelihood Functions; D008297:Male; D010375:Pedigree; D014842:von Willebrand Diseases / Q000235:genetics* / Q000503:physiopathology*
chemical_list: D006023:Glycoproteins