Although much research effort has been put into the development of new antidepressant drugs, the process of developing a drug often fails at the stage of large randomized controlled trials (RCTs)... Show moreAlthough much research effort has been put into the development of new antidepressant drugs, the process of developing a drug often fails at the stage of large randomized controlled trials (RCTs) in which an initially promising compound appears to lack efficacy after all. Several experimental medicine models have been proposed as preclinical tools in order to predict drug efficacy before the stage large RCTs. Among the various experimental medicine models, the cognitive neuropsychological model has been proposed as a tool to predict the efficacy of antidepressant drug even before the stage of large scale and expensive RCTs. We applied the cognitive neuropsychological model of drug action to test antidepressant effects of a novel compound (ARA290) and a well-known compound (L-tryptophan). We further investigated the model by tapping into HPA-axis reactivity and social decision making as additional outcomes, and investigated their interaction with a genetic marker. Show less
Aim of this thesis was to investigate pharmacogenetic effects on response to statin treatment and the genetics of lipid metabolism and cardiovascular disease. In chapter 4 the first results of the... Show moreAim of this thesis was to investigate pharmacogenetic effects on response to statin treatment and the genetics of lipid metabolism and cardiovascular disease. In chapter 4 the first results of the Genomic investigation of Statin Therapy (GIST) consortium are presented. We identified and validated two new GWAS loci to be associated with LDL-cholesterol response after statin treatment. In addition, we confirmed two previous identified loci. In chapter 5 we showed that we were not able to identify any loci associated with differential event reduction after statin therapy within the PROSPER study. The results presented in chapter 8 show that even at old age a genetic predisposition to high LDL-cholesterol is a risk factor for mortality. The results of this thesis show that currently the possibilities to personalize statin treatment based on genetic variants is limited. New research methods will hopefully give new opportunities to improve cardiovascular disease treatment and give more insight into the biological mechanisms of statin treatment. Show less
Rheumatoid Arthritis (RA) is a chronic autoimmune disorder that affects approximately 0.5-1% of the population. RA leads to inflammation of the joints and leads to irreversible destruction of... Show moreRheumatoid Arthritis (RA) is a chronic autoimmune disorder that affects approximately 0.5-1% of the population. RA leads to inflammation of the joints and leads to irreversible destruction of joints with subsequently to significant morbidity, disability for patients. Remarkably the amount of joint destruction differs substantially between patients. Currently medication mainly aims at diminishing inflammation. Because joint destruction seems to develop even when the inflammation level is low, since RA is still not curable and finally because joint destruction is irreversible, joint destruction becomes an increasingly important feature in patients with RA. In this dissertation, different aspects of joint destruction in RA were investigated. To highlight the most important findings: first of all the heritability of joint destruction was demonstrated. In addition several genes were further studied. Two genetic findings were of most interest: IL2RA was associated with joint destruction. Since there is already medication available that aims at IL2RA, this finding creates a new treatment option for the nearby future. More intriguingly, SPAG16, an thus far with sperm association gene, appears to be relevant in joint destruction in RA as well. This put a totally new light on the gene. Naturally, most of the newly discovered associations will need further research before they can be applied in clinical practice. Show less
Part I of this thesis starts with a description of the Leiden Early Arthritis Clinic, followed by chapters on predicting the progression from Undifferentiated Arthritis to Rheumatoid Arthritis (RA)... Show morePart I of this thesis starts with a description of the Leiden Early Arthritis Clinic, followed by chapters on predicting the progression from Undifferentiated Arthritis to Rheumatoid Arthritis (RA) and predicting the severity of RA by clinical information available early in the disease stage. In part II of this thesis, several studies to genetic factors underlying the differences in the severity of joint destruction, are presented. Most importantly, we report interesting associations between SNPs in the genes encoding Wnt-signalling proteins and the MMP-9 gene and progression of joint destruction. Part III of this thesis is devoted to ACPA-negative RA. Evidence is emerging that we should consider this a distinct pathofysiological entity from ACPA-positive RA. We also report the results of a Genome Wide Association Study (GWAS) to the radiographic progression of RA. In part IV of this thesis, we describe two studies to non-genetic factors that could influence the severity of RA. We did not find any clear seasonal differences for the season of RA onset. We also conclude that although smoking influences the long-term outcome of RA, the effect of smoking is not independent of ACPA-status. Show less
In this thesis I describe the developmental role of the Y-family polymerases Pol Eta, Pol Kappa and Rev1 in protection against exogenous and endogenous damage in C. elegans. Furthermore I identify... Show moreIn this thesis I describe the developmental role of the Y-family polymerases Pol Eta, Pol Kappa and Rev1 in protection against exogenous and endogenous damage in C. elegans. Furthermore I identify a new role for the A-family Polymerase Pol Theta in repair of replication-associated breaks. 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
Karakaya, B.; Vreeburg, M.D.; Megens, H.J.; van't Slot, R.; Bevova, M.; Ruven, H.J.T.; ... ; Moorsel, C.H.M. van 2013
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
