This thesis, titled __Genetic and pharmacogenetic determinants of cardiovascular disease__ is divided in three sections. In section one the genetic determinants of coronary restenosis are explored.... Show moreThis thesis, titled __Genetic and pharmacogenetic determinants of cardiovascular disease__ is divided in three sections. In section one the genetic determinants of coronary restenosis are explored. In the first genome-wide association study on this condition, in the GENetic DEterminants of Restenosis study, we describe a novel locus on chromosome 12 possibly associated with restenosis. Furthermore, by using several analysis tools on this data, we describe multiple biological pathways and genes that are likely associated with restenosis. In section two, we focus on genetic factors involved in three other (cardio)vascular diseases. We explore the role of DNA repair genes in myocardial infarction and stroke and the genetic determinants of dialysis shunt failure. Section three is on pharmacogenetics. In particular, we were interested in genetic variation involved in aspirin and clopidogrel resistance. We validated two genetic polymorphisms associated with recurrent thrombotic events during treatment with these agents in patients with an acute myocardial infarction. Genetic research is a fast developing field of research. By increasing our knowledge on the molecular background of diseases, genetics potentially could lead to more personalized treatment in the near future. Show less
Preeclampsia is a pregnancy-specific condition that originates in the placenta. Despite decades of research, its pathogenesis remains largely unknown. However, several risk factors for preeclampsia... Show morePreeclampsia is a pregnancy-specific condition that originates in the placenta. Despite decades of research, its pathogenesis remains largely unknown. However, several risk factors for preeclampsia have been identified, including a (family) history of preeclampsia, autoimmune disease and conditions associated with endothelial damage, including hypertension, diabetes mellitus and preexistent renal disease. This thesis aims to further investigate through which mechanisms these risk factors increase the risk for preeclampsia. It deals with both the genetic background of preeclampsia, as well as the role of complement activation in its pathogenesis. Finally, it touches upon the role of angiogenic factors in the development of preeclampsia. Show less
This thesis concerns the clinical and genetic aspects of familial thoracic aortic aneurysms and dissections, in particular in Marfan syndrome. It includes the Dutch multidisciplinary guidelines for... Show moreThis thesis concerns the clinical and genetic aspects of familial thoracic aortic aneurysms and dissections, in particular in Marfan syndrome. It includes the Dutch multidisciplinary guidelines for diagnosis and management of Marfan syndrome. These guidelines contain practical directions for referring physicians and specialists involved in the recognition, diagnosis, monitoring and treatment of Marfan syndrome. Furthermore, the revised Ghent nosology for Marfan syndrome, established by an international panel of experts, is presented. One chapter concerns a specific subgroup of missense mutations in FBN1 that are predicted to substitute the first aspartic acid of various calcium-binding Epidermal Growth Factor-like (cbEGF) fibrillin-1 domains. One of the mutations was found in a homozygous state in three cases from a large consanguineous family. A series of ten patients carrying a whole-gene deletion of one allele of FBN1 is described in another chapter. In a further chapter a three-generational family is discussed with family members at risk for serious aortic disease as a result of an interstitial deletion of chromosome 15 that disrupts SMAD3. Finally two unrelated children with classic Marfan syndrome and recurrent intracranial hypertension are described. Show less
Variation in structure and composition of the DNA are found throughout our genome. All types of variation are collectively called __genomic variation__. Identification and analysis of genomic... Show moreVariation in structure and composition of the DNA are found throughout our genome. All types of variation are collectively called __genomic variation__. Identification and analysis of genomic variation is important to distinguish neutral variants (__non pathogenic__) from variants involved in disease (__pathogenic__). Identification of new disease genes will increase our knowledge of the molecular pathogenesis of genetic disorders. Every technical advance in genetic analysis has revealed new levels of variation, ranging from single nucleotide differences to full chromosome changes. As new DNA methods are applied, increasing numbers of variants with unclear significance to disease (UVs) are identified and choices have to be made regarding the variants that deserve follow-up work. When the pathogenic consequence of a variant is unclear, the effect has to be studied in detail at other levels (functional studies, RNA studies, in silico analysis tools, and databases). The research described in this thesis outlines the rapid development and application of molecular techniques for detecting (pathogenic) genomic variation in the context of genetic disorders. Show less
