Evidence Of Possible Linkage Between Von Willebrand’S Disease (VWD) And 2 Polymorphic Genetic Markers

VWD shows great variability within and between families. In some kindred the affected persons show decreased amounts of an apparently normal VIIIR:Ag. In others, abnormal electrophoretic mobility of VIIIR:Ag has been associated with a defect in the degree of polymerization. Within kindred, expressivity may be so variable that some transmitters have normal laboratory findings. Detection of linkage between VWD and a clearly defined antigenic or biochemical marker might provide the means to make unambiguous diagnoses and to distinguish between the effects of the multiple genes involved in synthesis of VIIIR:Ag.

We have examined 4 VWD kindred, using 23 genetic markers. Individuals were classified for VWD using clinical and laboratory data, pedigree information and 2 statistical procedures: D I based on 3 measures of F VIII activity, and D II which also included bleeding time and a subjective index of symptoms. Using D I, a LOD score of 0.66 at a recombination frequency (θ) of 0.20 was found with GPT (glucose pyruvic transaminase). Using D II a LOD score of 0.50 at a θ of 0.25 was found. Most of the evidence of a VWD- GPT linkage was provided by a single kindred. Using D II, evidence suggesting a second linkage was observed between VWD and GLO (glyoxylase) with a LOD score of 1.03 at a 0 of 0.20, all 4 families contributing.

The LOD scores reported are suggestive of linkage and warrant further study. Since GLO relates to Chromosome 6 while the chromosomal location of GPT is not known and since GPT and GLO are unlinked, VWD may be genetically heterogeneous, 2 or more loci being involved.

Studies to clarify the relationship of VWD to Chromosome 6 are underway using markers known to be linked to GLO.