My thesis concerns different aspects of diabetic nephropathy. A pathologic classification of diabetic nephropathy is developed, a meta-analyis of genes in diabetic nephropathy is developed and the... Show moreMy thesis concerns different aspects of diabetic nephropathy. A pathologic classification of diabetic nephropathy is developed, a meta-analyis of genes in diabetic nephropathy is developed and the other chapters are about the CNDP1 gene in relation to kidney disease, mainly diabetic nephropathy. Show less
Colorectal cancer (CRC) is one of the most common cancers in the Western world and in about 30% hereditary factors play a role. Although several genetic factors that predispose families to CRC are... Show moreColorectal cancer (CRC) is one of the most common cancers in the Western world and in about 30% hereditary factors play a role. Although several genetic factors that predispose families to CRC are known, in many families affected with CRC the underlying genetics remain elusive. The work described in this thesis aimed to identify novel genetic factors that lead to an increased risk for CRC in these families. Several approaches were applied, including both germ line genetic analysis and the study of genomic aberrations in colorectal carcinomas. Linkage analysis did not provide evidence for a novel high risk factor, but provided supportive evidence for a previously identified region on 3q. Enrichment of common low risk variants was observed in a cohort of familial CRC patients but not in early-onset solitary patients (without a family history of CRC). Profiling of genomic aberrations in colorectal carcinomas showed distinct profiles for different hereditary CRC syndromes: MUTYH-associated carcinomas showed high frequencies of copy-neutral LOH. Mismatch repair proficient familial carcinomas appeared to resemble the genomic profile of sporadic CRC, but with a remarkably increased frequency of 20q gain and genome-wide cnLOH. Show less
In this thesis several aspects of metabolic syndrome are addressed. The focus involves questions concerning the genetics of obesity, TG and cholesterol and hyperglycemia. Since we hypothesized that... Show moreIn this thesis several aspects of metabolic syndrome are addressed. The focus involves questions concerning the genetics of obesity, TG and cholesterol and hyperglycemia. Since we hypothesized that obesity is the most important trigger of metabolic impairment, the MetS definition in this thesis was chosen to include the obesity measure waist circumference as an essential component. In the study described in chapter 2, the heritability of the metabolic syndrome was addressed and compared to the heritability of its individual components. Since the individual components of MetS were shown to be more heritable than MetS itself, the studies described in chapter 3 and 4 focused on the genetics of the individual MetS component plasma TG. For this purpose, a candidate gene approach was employed using HTG patients and healthy controls. The involvement of a series of candidate genes was confirmed. The study described in chapter 5 followed a similar approach to that used in the studies described in chapter 3 and 4. Several candidate genes were studied in patients suffering from hyperlipoproteinemia (HLP) type III, which is characterized by elevated levels of total plasma cholesterol and plasma TG. HLP type III is characterized by APOE2 homozygosity. Contributing genetic factors in the (metabolically stressed) APOE2/2 environment were confirmed. Plasma adiponectin, an adipose tissue secreted hormone (adipokine), has been suggested to be a biomarker for MetS. In chapter 6 we describe a study which particularly aimed to determine the effect of menopause on the discriminating accuracy of adiponectin to predict MetS. Especially low levels of plasma adiponectin in postmenopausal women were found to be a risk for MetS. However, the discriminating accuracy of adiponectin for the presence of MetS was exceeded by BMI in men and pre __and post menopausal women. Since plasma adiponectin levels are very well correlated with MetS components or related traits, the study described in chapter 7 addressed the question whether these correlations are caused by a genetic overlap (genetic correlation). The genetic correlation was mono-laterally validated with regard to the adiponectin gene (ADIPOQ). Chapter 8 describes a study towards finding novel loci associated with adiponectin or loci that are possibly involved in the genetic overlap between adiponectin and MetS components or related traits. This study followed a genome-wide association (GWA) approach. The results of this GWA were used in a joined analysis with two other cohorts in a meta-analysis. In addition, a selected proportion of SNPs was submitted for replication in several cohorts. Chapter 9 provides a general discussion by reviewing all previous chapters in the thesis. Furthermore, chapter 9 includes suggestions and proposals for future analyses towards unraveling genetic and environmental factors involved in the expression and manifestation of metabolic risk factors. Show less
Type 2 Diabetes (T2D) is a chronic disease, characterized by hyperglycaemia, caused by decreased insulin secretion by beta-cells and insulin resistance of target tissues of insulin. Several risk... Show moreType 2 Diabetes (T2D) is a chronic disease, characterized by hyperglycaemia, caused by decreased insulin secretion by beta-cells and insulin resistance of target tissues of insulin. Several risk factors are known, like decreased exercise, ageing and western diet. Also genetic variance can alter susceptibility to develop T2D. Until recently only four T2D susceptibility genes were identified (PPARG, KCNJ11, CAPN10 and TCF7L2). However, recent Genome Wide Association Studies (GWAS) have increased this number to at least 20. My thesis describes the search for additional T2D susceptibility genes. For this we used a classical candidate gene approach and we case/control studies from the Netherlands, Scandinavia and the UK. We selected 14 nuclear encoded candidate genes, all regarded essential for mitochondrial protein synthesis and biogenesis. Since mitochondrial function was shown to be associated with T2D, we hypothesized that genes in these pathways are good candidates. Tagging SNPs were selected, which should cover all known common variation (minor allele frequency (MAF) > 0.05) in the candidate genes. These tagging SNPs were measured in our first stage, comprising of the Dutch Hoorn study and significant associations were than taking forward for replication in our replication cohorts in the second stage of this study. However, after second stage genotyping non of the signals remained significant, indicating that the selected candidate genes do not play a major role in T2D susceptibility. Furthermore, nuclear encoded mitochondrial genes were not among the top hits of GWAS, which were made available online after completion of our study. Therefore, we conclude that nuclear encoded mitochondrial genes do not have a major contribution to the development of T2D. Next, we analyzed the association of mitochondrial DNA (mtDNA) content with T2D. First we estimated the heritability in Dutch twins and found a heritability of 35% (19%-48%). Next we analyzed the association with prevalent and incident T2D in a Dutch case control study and two prospective studies from the Netherlands and Finland. However, no associations were observed. Therefore, we conclude that mtDNA content does not play a major role in the development of T2D. Finally, we analyzed four known fasting plasma glucose (FPG) influencing genes (GCK, GCKR, G6PC2 and MTNR1B). In a Dutch population based sample we could replicate the association of these genes with FPG levels (except for GCKR). Furthermore, the combined risk alleles (ranging from 0 to 8 risk alleles) were strongly associated with FPG and HbA1C levels. This risk allele score was also associated with T2D susceptibility and age of diagnosis at T2D. We therefore conclude that the FPG influencing genes have a combined effect on FPG and are associated with T2D susceptibility and age at diagnosis of T2D. In conclusion, we could not find evidence that nuclear encoded mitochondrial proteins and mtDNA content are associated with T2D susceptibility. The four known FPG genes do not only influence FPG levels, but also have a combined effect on T2D susceptibility and age at diagnosis of T2D. Show less
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
This thesis describes the search for new high-risk breast cancer susceptibility genes by linkage analysis. To date 20-25% of familial breast cancer is explained by mutations in the high-risk BRCA1... Show moreThis thesis describes the search for new high-risk breast cancer susceptibility genes by linkage analysis. To date 20-25% of familial breast cancer is explained by mutations in the high-risk BRCA1 and BRCA2 breast cancer susceptibility genes. For the remaining families the genetic etiology is unknown. It is still possible that other high-penetrant genes play a role. Although a polygenic model with multiple low-penetrant genes acting additive or multiplicative will probable explain most of the BRCA1/2 negative families. Linkage in an international set of 150 high-risk breast cancer families couldn__t identify high-risk genes. However when limiting the linkage analysis to Dutch families only, we identified 9q21-22 as a putative breast cancer susceptibility locus Show less
Linkage analysis makes use of genetic markers to measure genetic similarity between relatives. By comparing this index of genetic similarity with phenotypic similarity, we can identify chromosomal... Show moreLinkage analysis makes use of genetic markers to measure genetic similarity between relatives. By comparing this index of genetic similarity with phenotypic similarity, we can identify chromosomal regions harbouring genes involved in the architecture of a phenotype of interest. Although linkage has been very successful in discovering genes responsible for simple Mendelian diseases, results have often been disappointing in gene mapping for complex traits. This thesis presents some attempts to improve the current design and analysis of linkage studies for complex traits. The statistical methodology adopted is driven by the fact that genes involved in complex traits have small effects, it therefore seems legitimate to use score tests because of their local optimality properties. In addition, score tests often give rise to tractable expressions, in the context of linkage these can be meaningfully interpreted in terms of regressions and quickly computed which is a crucial feature in genetics. Show less
This thesis investigated the association between several genetic factors and autoantibodies and the development of undifferentiated arthritis (UA) and rheumatoid arthritits (RA). Second, this... Show moreThis thesis investigated the association between several genetic factors and autoantibodies and the development of undifferentiated arthritis (UA) and rheumatoid arthritits (RA). Second, this thesis described a prediction model that estimates the chance to progress from UA to RA. The most important genetic risk factor for RA are the HLA-Class II alleles that encode for a common amino acid sequence, called the ‘Shared Epitope’. Investigating the progression to RA from UA revealed that the HLA-Shared Epitope alleles are not primarily a risk factor for RA but for the presence of anti-CCP antibodies, that are known to be specific for RA. Smoking in the presence of HLA-Shared Epitope alleles particularly increased the risk on anti-CCP-positive RA.. The HLA-DR3 alleles were associated with anti-CCP-negative RA. The presence of HLA-alleles encoding for D70ERAA correlated with a lower risk on RA and a less severe disease course. The presence of the PTPTN22 T-allele conferred an increased risk for both UA and RA. The knowledge on risk factors for RA-development was translated in a model that estimates the chance to progress to RA in patients that present with UA by using 9 clinical variables. The discriminative ability was high and this model allows individualized treatment decisions in UA. Show less
This thesis examines different risk factors, in relation to restenosis after Percutaneous coronary interventions (PCI), with its main focus on genetic markers. Restenosis is the main drawback of... Show moreThis thesis examines different risk factors, in relation to restenosis after Percutaneous coronary interventions (PCI), with its main focus on genetic markers. Restenosis is the main drawback of PCI. Genetic variance poses an opportunity to enhance stratification of individuals who will be more prone to develop restenosis. Restenosis is a multifactorial process, therefore only limited part of the number of candidate genes that are potentially involved in restenosis can be described. Since the inflammatory reaction is known to be highly important in restenosis, our study has its main focus on inflammatory markers. To examine various candidate genes and their polymorphisms we made use of the GENetic DEterminants of Restenosis (GENDER) study, a multicenter follow-up study, including 3,104 consecutive patients, who were successfully treated with PCI. In the different chapters we describe the study population and the clinical and genetic factors investigated. Furthermore, we made use of a mouse model to improve our understanding of restenosis. Our results have contributed to a better understanding of the restenotic process, they could provide novel therapeutic targets as well as contribute to development of improved risk stratification of patients who are scheduled for elective PCI, thereby creating the opportunity to individualize treatment in the future. Show less
Venous thrombosis is a well-known complication of central vein catheters (CVCs), which may cause serious morbidity and may result in potentially lethal complications such as pulmonary embolism. In... Show moreVenous thrombosis is a well-known complication of central vein catheters (CVCs), which may cause serious morbidity and may result in potentially lethal complications such as pulmonary embolism. In this thesis the general risk of CVC related thrombosis has been assessed, i.e., what is the overall risk of developing CVC related thrombosis? Which patients are prone to develop thrombosis with its associated morbidity? Are we able to predict this risk by routine surveillance in "high-risk" patients? Better knowledge of the incidence of CVC related thrombosis and identification of high-risk groups will assist clinicians in decision making about CVC use in the various patient-groups and in whom anticoagulant prophylaxis may be warranted. In summary, the a priori determination of common inherited and acquired risk factors may form a basis to guide (prophylactic) treatment decisions. Vulnerable patients may benefit the most, i.e. those who have a high risk of clinically manifest thrombosis, and who are at risk of hemorrhage, such as patients who undergo intensive chemotherapy. Besides, surveillance of these patients with screening by ultrasound, or alternatively surveillances cultures, may be useful to identify patients at high or low risk for clinically manifest CVC related thrombosis, and focused early intervention may be initiated. Show less
