The aim of this thesis was to identify novel lifespan regulating loci that influence human longevity and population mortality. To this end, we performed two genome-wide association studies, one of... Show moreThe aim of this thesis was to identify novel lifespan regulating loci that influence human longevity and population mortality. To this end, we performed two genome-wide association studies, one of long-lived individuals from the family-based Leiden Longevity Study (LLS) and an extended one of long-lived individuals from multiple cohorts of European descent. Using the latter, we identified two genome-wide significant loci, the TOMM40/APOE/APOC1 locus and an intergenic locus on chromosome 5q33.3. In addition, our gene set analysis with the LLS data showed that genetic variation in genes involved in the insulin/IGF-1 signaling and telomere maintenance pathways is associated with human longevity. Since our genetic studies identified a limited number of longevity loci, we additionally examined whether leukocyte telomere length (LTL) could be used as a biomarker of healthy aging. We showed that LTL meets three of the four criteria for a biomarker of healthy aging in the LLS, i.e., LTL changes with chronological age and is associated with health, in this case immune-related parameters, and prospective mortality. To identify novel longevity loci, future research may benefit from a better definition of the healthy aging phenotype, combining study designs, and the use of novel methods and technologies, such as next-generation sequencing. 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
