An association of candidate gene haplotypes and bleeding severity in von Willebrand disease type 2A, 2B, and 2M pedigrees

Abstract

Summary. 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 ¼ 0.012) or when genderspecific 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 a 2 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.

von Willebrand disease (VWD): evidence‐based diagnosis and management guidelines, the National Heart, Lung, and Blood Institute (NHLBI) Expert Panel report (USA)1

“…In persons with type 1 VWD, the FVIII level is often slightly higher than the VWF level and may fall within the normal range. In persons with type 2 VWD (except for type 2N VWD in which it is decreased), the FVIII is often two to three times higher than the VWF activity (VWF:RCo) [162,163]. Therefore, the PTT is often within the normal range.…”

Type 2M and Type 2A von Willebrand Disease: Similar but Different

“…Kunicki et al 63 examined the major haplotypes of seven candidate genes (GP1BA, ITGA2B, ITGB3, GP6, VWF, FGB, and IL6) but found that only genetic differences in expression of ITGA2B encoding integrin subunit α2 of platelet collagen receptor were associated with bleeding phenotype in type 2 VWD. Favaloro et al also raised the question of whether the increased gastrointestinal bleeding may represent a failure of VWF-collagen interaction based on the different pathophysiology in these two VWD subtypes.…”

Bleeding scores in inherited bleeding disorders: clinical or research tools?

“…A significant difference in BS was observed between carriers and non‐carriers of the haplotype, a finding that could be relevant in explaining some of the variations related to bleeding in VWD. Using the same bleeding score, the ITGA2 haplotype was also found to be associated with bleeding severity in 11 families with type 2 VWD [22].…”