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 (VT) is a common disease, which occurs mostly in the deep veins of the leg. VT clusters within families and is a multicausal disease, in which both genetic and environmental... Show moreVenous thrombosis (VT) is a common disease, which occurs mostly in the deep veins of the leg. VT clusters within families and is a multicausal disease, in which both genetic and environmental factors interact in the onset of the disease. The aim of the study described in this thesis was to find new genetic risk factors for VT. To identify these new genetic risk factors, we used a haplotype-based candidate gene approach. The main hypothesis of this approach was that relatively common functional variants exist that are the product of unique mutational events in a founder haplotype and that the frequency of such haplotypes will be increased in a patient population. In this thesis, candidate genes were selected on the basis of theoretical knowledge of the proteins encoded by the genes. The candidate gene investigated are the Endothelial cell Protein C Receptor (EPCR) (Chapter 2), Fibrinogen (Chapter 3), and the genes of the selectin family (E-selectin (SELE), L-selectin (SELL) and P-selectin (SELP)) and their most important counter-receptor P-selectin ligand (PSGL-1). The results described in this thesis may contribute to a better understanding of the etiology of VT.Venous thrombosis (VT) is a common disease, which occurs mostly in the deep veins of the leg. VT clusters within families and is a multicausal disease, in which both genetic and environmental factors interact in the onset of the disease. The aim of the study described in this thesis was to find new genetic risk factors for VT. To identify these new genetic risk factors, we used a haplotype-based candidate gene approach. The main hypothesis of this approach was that relatively common functional variants exist that are the product of unique mutational events in a founder haplotype and that the frequency of such haplotypes will be increased in a patient population. In this thesis, candidate genes were selected on the basis of theoretical knowledge of the proteins encoded by the genes. The candidate gene investigated are the Endothelial cell Protein C Receptor (EPCR) (Chapter 2), Fibrinogen (Chapter 3), and the genes of the selectin family (E-selectin (SELE), L-selectin (SELL) and P-selectin (SELP)) and their most important counter-receptor P-selectin ligand (PSGL-1). The results described in this thesis may contribute to a better understanding of the etiology of VT. Show less
