Novel genetic risk factors for venous thrombosis; a haplotype-based candidate gene approach

Abstract

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.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.Dutch Heart Foundation, Dr. Ir. Van der Laar Stichting, J.E. Jurriaanse Stichting, EurogentecUBL - phd migration 201