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 inflammation of several joints caused by autoimmunity. HLA molecules are most important risk factor involved in RA development. Regarding the risk of RA... Show moreRheumatoid arthritis (RA) is a chronic inflammation of several joints caused by autoimmunity. HLA molecules are most important risk factor involved in RA development. Regarding the risk of RA development, three variants can be discriminated; the shared epitope increases the risk, DERAA-containing HLA molecules decrease the risk and a neutral variant. In this thesis we describe that a mother, in contrast to a father, with a DERAA-containing HLA-molecule confers a life-long protection to her child against RA development with and without passing the gene responsible for the HLA-molecule. Furthermore, we describe that the T cells of HLA-DR4 positive RA patients can react against certain peptides derived from the citrullinated (a post-translational modification) vimentin protein in a citrulline-specific manner. Next to HLA-molecules there are several other genetic factors involved in the risk of RA development, e.g. PTPN22 and CD40. For the PTPN22 SNP associated with RA development, we showed that information on the presence of the PTPN22 SNP next to the presence of ACPA (antibodies specific for RA patients) does not give additive value to the prediction of RA development. On the contrary, the SNP has an influence on the level of ACPA present in the patient. For a SNP in the CD40 gene, we showed that it influences the severity and progression of RA. Show less
Venous thrombosis results from blood coagulation in veins, most frequently in the deep veins of the leg. Risk factors for venous thrombosis may be environmental or genetic; in most cases venous... Show moreVenous thrombosis results from blood coagulation in veins, most frequently in the deep veins of the leg. Risk factors for venous thrombosis may be environmental or genetic; in most cases venous thrombosis occurs after an environmental trigger on a background of increased susceptibility. This thesis describes research into the genetic variability that determines why some are more prone to develop venous thrombosis than others. Known genetic variants and the family history of venous thrombosis were evaluated as risk factors, and new variants were identified in a large association study of thousands of single nucleotide polymorphisms. Finally, the possibility of genetic profiling was explored, making use of known and newly identified genetic variants. Show less
The lifespan of an organism is determined by a complex network of environmental-, genetic- and stochastic factors. Each of these components contributes to the wide variability in lifespan between... Show moreThe lifespan of an organism is determined by a complex network of environmental-, genetic- and stochastic factors. Each of these components contributes to the wide variability in lifespan between and within species. In recent years, it has been shown that 20-30 % of human lifespan is under genetic control. Furthermore, a number of longevity candidate genes have been identified. The majority of candidate genes have emerged from studies with model organisms, but also from the biology of human ageing. The objective of this thesis was to test the impact of the most prominent longevity candidate genes on the prevalence of age-related diseases and lifespan in humans. All studies presented in this thesis were performed within the Leiden 85-plus Study, which is a population-based prospective study of the oldest old. The results revealed that genetic variations in most of the candidate genes influence metabolism, prevalence of age-related diseases, cognitive functioning and lifespan. Therefore, the approach of analyzing the most prominent longevity candidate genes in humans, contributes to the identification of biological mechanisms that influence the prevalence of disease in old age and lifespan. Show less
Genetic factors play an important role in the regulation of human life span but the exact pathways remain to be elucidated, however they may be interrelated with the regulation of human... Show moreGenetic factors play an important role in the regulation of human life span but the exact pathways remain to be elucidated, however they may be interrelated with the regulation of human reproduction. It is argued that an innate cytokine profile supportive of Th1-type T cells favors survival of infectious diseases (with longevity as the ultimate), but women with this profile are found less likely to have successful pregnancies (progeny). The probability of a normal fertility was found to increase more than 10-fold when the innate cytokine profile was characterized by high IL-10 (Th-2 cytokine) and low TNF- (Th-1 cytokine) responsiveness. The IL10 –2849 AA genotype was found to be associated with a decreased fertility and fecundity (time to pregnancy) in females, possibly due to the lower expected IL10 responsiveness. Rheumatoid arthritis (RA) is an example of a Th-1 mediated disease. It was found that the phenotype of joint destruction in RA was associated with the phenotype of reported miscarriages, suggesting common genetic risk factors for each of these two traits, possibly through the innate Th-1/Th-2 phenotype. Factor V Leiden (FVL) is a point mutation in the factor V gene generating a 7-fold increase in incidence of deep vein thrombosis. Specific advantages of the FVL mutation in early pregnancy (implantation) might balance its potentially harmful effects later in life and explain the remarkably high prevalence of this mutation in the general population. Show less
