Genetic determinants of venous thrombosis

Abstract

Venous thrombosis (VT), the occlusion of the venous system by a blood clot, is a multicausal disorder affecting 1-2 per 1000 individuals annually. The risk of VT and its complications is not equal for all individuals. In addition to clinical or acquired risk factors, genetic variation contributes to the risk of venous thrombosis. So far, variation in seventeen genes, almost all encoding proteins related to hemostasis, have consistently been identified as genetic risk factors for a first venous thrombosis. Evidence from previous genome-wide association studies and family studies suggests that additional genetic risk variants are yet to be discovered. In addition, the extent to which the identified risk variants contribute to recurrence risk is not clear, nor whether different genetic risk factors play a role in recurrence pathophysiology than those involved in a first event. In this thesis, we used various strategies to identify variants across the allele frequency spectrum that are associated with the risk of a first or recurrent venous thrombosis. In addition, we investigated whether previously identified genetic risk variants can be used to improve risk stratification for venous thrombosis and we discussed the potential value of using genetic variation to aid causal inferences in observational research.