Genetic screening of candidate genes for a prothrombotic interaction with type I protein C deficiency in a large kindred

The incomplete penetrance of thrombosis in familial protein C deficiency su ggests disease occurs when this deficit is combined with additional abnorma lities in the hemostatic system. The pattern of inherited thrombophilia in the Vermont II kindred, which is affected by a clinically dominant type I p rotein C deficiency, provides strong evidence for a second unidentified gen e that segregates independently of protein C deficiency and increases susce ptibility to thrombosis. To test the second gene hypothesis, thirty-four ca ndidate genes for proteins involved in hemostasis or inflammation were test ed as the unknown defect, using highly polymorphic short tandem repeat (STR ) markers in an informative subset (n = 31) of the kindred. The genes consi dered are; alpha -fibrinogen, beta -fibrinogen, gamma -fibrinogen, prothrom bin, tissue factor, factor V, protein S, complement component 4 binding pro tein, factor XI, factor XII, factor XIIIa, factor XIIIb, histidine rich gly coprotein, high molecular weight kininogen, kallikrein, von Willebrands fac tor, platelet factor 4, thrombospondin, antithrombin III, alpha -1-antitryp sin, thrombomodulin, plasminogen, tissue plasminogen activator, urokinase p lasminogen activator, plasminogen activator inhibitor-1, plasminogen activa tor inhibitor-2, protein C inhibitor, alpha -2-plasmin inhibitor, kallistat in, lipoprotein a, interleukin 6, interleukin 1,cystathionine-beta -synthas e, and methylenetetrahydrofolale reductase. Mutations in many of these gene s have been previously established as independent risk factors for thrombos is. However, linkage analysis provided no evidence to implicate any of the candidate genes as the second inherited factor that promotes thrombophilia in this kindred.