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

ABSTRACTVon 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 fourteen i ndex cases, using a covariance components model for multivariate traits (Mendel: QTL Association). The se 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 nine 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=0.00009 and p = 0.00496, respectively). GP6haplotype b (Pro 219 ) was also associated with increased scores (p = 0.02912) after adjustment for donor age. No association was observed with six other candidate genes, GP1BA, ITGB3, VWF, FGB, IL6 or TXA2R. Increased plasma VWF:Ag levels were associated with VWF haplotype 1 (-1793G) (p=0.02314). These results establish that genetic differences in the adhesion receptor subunits