Venous thrombosis (VT) is a multicausal disease that is caused by the interaction of both genetic and acquired risk factors. The aim of the studies described in this thesis was to identify novel... Show moreVenous thrombosis (VT) is a multicausal disease that is caused by the interaction of both genetic and acquired risk factors. The aim of the studies described in this thesis was to identify novel genes or genomic regions that contribute to the susceptibility of VT. We used two different approaches to achieve this goal: the hypothesis-based candidate gene approach and the discovery-based genome-wide approach. The candidate genes investigated are factor VII-activating protease, coagulation factor IX and four interleukin-1 related genes. As a second approach we used a genome-wide linkage approach to systematically scan the genome for genes or genomic regions that contribute to the susceptibility of venous thromboembolism (VTE). For this purpose we recruited a panel of affected sibling pairs with VTE at a young age (Genetics In Familial Thrombosis study, GIFT). Two novel susceptibility regions for VTE were identified. We screened eleven candidate genes, selected from both regions, to investigated whether variants of these genes could explain the observed linkage signals. Identification of the gene(s) and their functional variants, which are responsible for the linkage signals, will give better insights in the molecular genetics of familial thrombophilia and might be important for the diagnosis, treatment and prevention of VTE. Show less
Venous thrombosis is a common disease, which manifests itself mostly in the deep veins of the leg, with a reported incidence of 1-2 per 1000 individuals per year. Several genetic risk factors have... Show moreVenous thrombosis is a common disease, which manifests itself mostly in the deep veins of the leg, with a reported incidence of 1-2 per 1000 individuals per year. Several genetic risk factors have been identified for venous thrombosis. It is, however, difficult to predict the risk of venous thrombosis for carriers of these defects, as venous thrombosis manifests itself as a multicausal disease, in which multiple genetic and environmental factors play a role and can interact in the onset of disease. In families with a clear tendency to develop venous thrombosis (thrombophilia) the presence of multiple genetic risk factors explains the higher risk in individuals from these families compared with individuals with the same defect without a family history of venous thrombosis. Large studies on the risk of venous thrombosis associated with familial thrombophilia are scarce, therefore we initiated a large European prospective cohort study including individuals with inherited thrombophilia: the EPCOT study. Data from this study showed that the risk of a first or second thrombotic event was increased in carriers of familial thrombophilic defects, but that the risk did not outweigh the risk of major bleeding from long-term anticoagulant treatment. In addition the EPCOT study showed that women with inherited thrombophilia have a slightly increased risk of fetal loss. However, the likelihood of a positive outcome remained high in women with familial thrombophilia. In addition, as the currently known genetic defects can explain only partly the increased risk of venous thrombosis in thrombophilic families, we performed a search for "new" genes that might regulate blood plasma levels of coagulation factors in a large thrombophilic French-Canadian family. We found high heritability (i.e. the amount of variation of levels explained by gene variation) for several coagulation factors and we identified gene locations that might harbour genes influencing protein C activity. Show less
