Rheumatoid Arthritis (RA) is a chronic autoimmune disease, affecting a ~1% of the population worldwide. Although its causes are largely unknown, a considerable heritable component approximating 50... Show moreRheumatoid Arthritis (RA) is a chronic autoimmune disease, affecting a ~1% of the population worldwide. Although its causes are largely unknown, a considerable heritable component approximating 50-60% has been described. The most prominent genetic association in RA is confined to the human leukocyte antigen (HLA) locus which has been known for ~30 years. The identification of RA-associated genes outside of the HLA region, however, had been a challenge. A few years ago, one such gene, protein tyrosine phosphatase, non-receptor type 22 (lymphoid), was identified in a large genetic-association study utilizing putative functional SNPs. The aim of this thesis was to take a candidate gene approach to identify risk factors involved in rheumatoid arthritis. It is divided into three parts in which part one is dedicated towards the identification of a novel risk factor for RA and autoimmunity. This region of the genome encompasses genes highly involved in the immune system, namely Tumour Necrosis Factor Receptor associated factor 1/Complement component 5 on chromosome 9q33. In the second part, we have investigated the role of an immunoregulatory cytokine interleukin 10 located on chromosome 1q32 and in part three we have investigated the role of additional genetic risk factors in RA. Show less
The research described in this thesis consist of 2 parts: the first part involves studies on the influence of chemokines in cardiovascular disease. Chemokines are inflammatory proteins which play a... Show moreThe research described in this thesis consist of 2 parts: the first part involves studies on the influence of chemokines in cardiovascular disease. Chemokines are inflammatory proteins which play a pivotal role in atherosclerosis and myocardial ischemia. We identify 3 chemokines (CCL3, CCL5 and CCL18) whose levels are not only elevated during myocardial ischemia, but are also predictive of future cardiovascular events. Further studies focus on the individual role of CCL18 as well as CCL3 in atherogenesis and atherosclerotic plaque destabilization. The first is seen to recruit T-lymphocytes and the latter neutrophil granulocytes into the plaque, possibly augmenting plaque growth and destabilization. The second part focuses on the effect of gene modulation on vascular function. It start of with a study on the influence of aging in our atherosclerotic plaque mouse model. Additional genetic microarray revealed the Quaking gene as a possible modulator of atherosclerosis. This observation is further explored in studies which show a link between Quaking genetic polymorphisms and an enhanced risk of developing in-stent restenosis following percutaneous coronary intervention. This is partly mediated by disturbed vascular smooth cell function. Finally, the MEF2 gene is studied for its role in myocardial infarction as genetic mutations in the MEF2A gene are associated with enhanced risk for a myocardial infarction. In a mouse model, we show that this is primarily due to decreased endothelial cell function, leading to plaque erosion. Show less
The thesis “Non-motor symptoms in Parkinson’s disease” is part of the PROPARK study, a longitudinal cohort study of approximately 400 patients with Parkinson’s disease (PD), who are profiled on... Show moreThe thesis “Non-motor symptoms in Parkinson’s disease” is part of the PROPARK study, a longitudinal cohort study of approximately 400 patients with Parkinson’s disease (PD), who are profiled on genotype, phenotype, disability, and global outcomes of health, using valid and reliable assessment instruments for PD. The aims of this thesis were to characterize the non-motor domains important in PD such as olfactory, autonomic, sleep, cognitive, and psychiatric problems. Additionally, their relations with other domains of the disease were evaluated on a cross-sectional level, as well as their impact on disability and health-related quality of life. Furthermore, the phenotypic characteristics of mutation carriers in the cohort were evaluated. The most important conclusions from this thesis are: 1. Non-motor symptoms are frequently present in patients with PD 2. Non-motor symptoms are related to each other 3. Non-motor symptoms greatly influence quality of life in patients with PD The results as described in this thesis will serve as guideline for future research which will be aimed at underlying disease mechanisms. Show less
