title: An association of candidate gene haplotypes and bleeding severity in von Willebrand disease type 2A, 2B, and 2M pedigrees.
abstract: We analyzed the association of bleeding severity with candidate gene haplotypes within pedigrees of 11 index cases of von Willebrand disease (VWD) type 2 (two type 2A, three type 2B and six type 2M), using the QTL Association model (MENDEL 5.5). In addition to the 11 index cases, these pedigrees included 47 affected and 49 unaffected relatives, as defined by VWF mutations and/or phenotype. A bleeding severity score was derived from a detailed history and adjusted for age. Donors were genotyped using a primer extension method, and eight candidate genes were selected for analysis. VWF antigen (or ristocetin cofactor activity) levels had the strongest influence on bleeding severity score. After Bonferroni correction for multiple testing, only ITGA2 promoter haplotype -52T was associated with an increased bleeding severity score (P < 0.01). This association remained statistically significant when the three type 2B pedigrees were excluded (P = 0.012) or when gender-specific bleeding categories were excluded (P < 0.01). The major haplotypes of seven other candidate genes, GP1BA, ITGA2B, ITGB3, GP6, VWF, FGB, and IL6, were not associated with bleeding severity. These results establish that genetic differences in the expression of the integrin subunit alpha2 can influence the bleeding phenotype of VWD type 2 and complement our previous findings in VWD type 1. Genetically controlled attenuation of platelet collagen receptor expression can influence risk for morbidity in clinical settings where hemostasis is compromised.
authors.affiliation: Department of Molecular and Experimental Medicine, The Division of Experimental Hemostasis and Thrombosis, The Scripps Research Institute, La Jolla, CA 92037, USA. tomk@scripps.edu
authors.forename: T J
authors.initials: TJ
authors.lastname: Kunicki
authors.forename: L
authors.initials: L
authors.lastname: Baronciani
authors.forename: M T
authors.initials: MT
authors.lastname: Canciani
authors.forename: F
authors.initials: F
authors.lastname: Gianniello
authors.forename: S R
authors.initials: SR
authors.lastname: Head
authors.forename: T S
authors.initials: TS
authors.lastname: Mondala
authors.forename: D R
authors.initials: DR
authors.lastname: Salomon
authors.forename: A B
authors.initials: AB
authors.lastname: Federici
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006470:Hemorrhage / Q000235:genetics*; D006801:Humans; D039421:Integrin alpha2 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008957:Models, Genetic; D009154:Mutation; D010375:Pedigree; D011401:Promoter Regions, Genetic; D012720:Severity of Illness Index; D014842:von Willebrand Diseases / Q000097:blood / Q000235:genetics*; D014841:von Willebrand Factor / Q000235:genetics
chemical_list: D039421:Integrin alpha2; D014841:von Willebrand Factor