AN UNKNOWN GENETIC-DEFECT INCREASES VENOUS THROMBOSIS RISK, THROUGH INTERACTION WITH PROTEIN-C DEFICIENCY

We used two-locus segregation analysis to test whether an unknown gene tic defect interacts with protein C deficiency to increase susceptibil ity to venous thromboembolic disease in a single large pedigree. Sixty -seven pedigree members carry a His107Pro mutation In the protein C ge ne, which reduces protein C levels to a mean of 46% of normal. Twenty- one carriers of the mutation and five other pedigree members had verif ied thromboembolic disease. We inferred the presence in this pedigree of a thrombosis-susceptibility gene interacting with protein C deficie ncy, by rejecting the hypothesis that the cases of thromboembolic dise ase resulted from protein C deficiency alone and by not rejecting Mend elian transmission of the interacting gene. When coinherited with prot ein C deficiency, the interacting gene conferred a probability of a th rombotic episode of similar to 79% for men and similar to 99% for wome n, before age 60 years.