An association of candidate gene haplotypes and bleeding severity in von Willebrand disease (VWD) type 1 pedigrees

Thomas J. Kunicki, Augusto B. Federici, Daniel R. Salomon, James A. Koziol, Steven R. Head, Tony S. Mondala, Jeffrey D. Chismar, Luciano Baronciani, Maria Teresa Canciani, Ian R. Peake

Research output: Contribution to journalArticlepeer-review

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 (Ile843) were each associated with increased bleeding severity scores (P <.01 and P <.01, respectively). GP6 haplotype b (Pro219) 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 α2, αIIb, and GPVI can influence the phenotype of VWD type 1.

Original languageEnglish
Pages (from-to)2359-2367
Number of pages9
JournalBlood
Volume104
Issue number8
DOIs
Publication statusPublished - Oct 15 2004

ASJC Scopus subject areas

  • Hematology

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