In this thesis, we aimed to better understand how genetic variation affect the processes underlying health and disease, as trait-associated genetic variants are often located in non-coding... Show moreIn this thesis, we aimed to better understand how genetic variation affect the processes underlying health and disease, as trait-associated genetic variants are often located in non-coding regions. This hampers their interpretability, and has prompted the exploration of their effects on transcriptional regulation, a process that is crucial in the development of common and complex diseases. To do this, we have used a variety of omics data in a large collection of individuals from the general population. Using these data, we have investigated the local and distal effects of genetic variants on other molecular phenotypes, such as gene expression levels and DNA methylation levels of CpG sites, and the underlying mechanisms. This has resulted in a framework enabling the exploration of causal hypotheses about transcriptional regulation using genetics as a causal anchor. The approaches used in this thesis have yielded insight into transcriptional (dys)regulation and several underlying mechanisms. This will be helpful in better understanding how transcriptional regulation contributes to complex phenotypes related to health and disease, such as common diseases. Show less
Thrombosis is considered to be a multifactorial disease in which both genetic and acquired risk factors are involved to cause disease. Over the past years epidemiological studies have revealed a... Show moreThrombosis is considered to be a multifactorial disease in which both genetic and acquired risk factors are involved to cause disease. Over the past years epidemiological studies have revealed a number of acquired risk factors that increase the risk of venous thrombosis. Some acquired risk factors of venous thrombosis are associated with a hypercoagulable state, which may be to a certain extent dependent on the dysregulation of gene expression in the liver, as the liver is the major organ that produces coagulation factors. Coagulation gene transcription can be modulated at different levels through hepatic transcription factors, co-regulatory or intermediate proteins, however, the exact contribution of these modulators to coagulation gene transcription is largely unknown. We aimed to study the mechanisms by which hepatic coagulation gene transcription is regulated, in order to increase our understanding of how thrombotic risks conditions coincide with hypercoagulable state. RNA interference (via synthetic small interfering RNA; siRNA) was used as a tool to study genes involved in coagulation and coagulation control in mice. Studies described in this dissertation may contribute to a better understanding of which genes are involved in coagulation (control) and how thrombotic risk factors result in a hypercoagulable state Show less
Over the years, a number of acquired risk factors for venous thrombosis have been identified in large epidemiological studies. We aimed to identify the biological mechanisms by which acquired risk... Show moreOver the years, a number of acquired risk factors for venous thrombosis have been identified in large epidemiological studies. We aimed to identify the biological mechanisms by which acquired risk factors like female hormones, thyroid hormone and obesity result in a hypercoagulable state and increased risk for venous thrombosis, since these are currently poorly understood. As these risk factors are all, to a certain extent, able to interfere with liver metabolism we hypothesized that they modulate hepatic transcription of coagulation genes, either directly via nuclear hormone receptors and hormone response elements in target genes (female hormones and thyroid hormone), or indirectly as a result of altered liver homeostasis (obesity). To study these hypotheses, we used an in vivo approach, which not only gives the opportunity to study the risk factor-mediated transcriptional modulation of coagulation genes, but also allowed us to study the relation between transcriptional changes on the one hand and plasma protein levels and a thrombotic tendency on the other. The data presented in this thesis clearly demonstrate that modulation of hepatic coagulation gene transcription is a key mechanism by which acquired risk factors for venous thrombosis impact the hemostatic balance. Show less
Activation of microglia, the macrophages of the central nervous system, is a key element in multiple sclerosis (MS) lesion development and is characterized by enhanced expression of both classes of... Show moreActivation of microglia, the macrophages of the central nervous system, is a key element in multiple sclerosis (MS) lesion development and is characterized by enhanced expression of both classes of major histocompatibility complex (MHC) molecules. This enhanced expression results from increased levels of several transcription factors involved in MHC gene expression. In addition, microglial activation in MS is characterized by enhanced motility. We show that the expression of the chemokine receptor CCR5, a mediator of cell movement, is increased on microglia, macrophages and astrocytes in MS lesions. Additionally, we have determined that CCR5 transcription is regulated by the transcription factor CREB-1, which is also involved in MHC gene expression, and is highly expressed in MS lesions. Because of their immunomodulatory properties, statins (cholesterol lowering drugs) are recently being considered as a possible treatment for MS. We have determined that statins decrease expression of amongst others MHC and CCR5 molecules by inhibiting the transport of these molecules to the cell surface. In addition, we show that statins reduce the motility of microglia and inhibit the differentiation of blood-derived monocytes into dendritic cells, indicating that statins indeed affect critical immune functions and might prove to be beneficial for treatment of MS patients. Show less
