Metabolomics, proteomics, and genomics analyses provide profound insight into human biology and disease pathophysiology. In this thesis, we explored the methodological challenges facing these OMICs... Show moreMetabolomics, proteomics, and genomics analyses provide profound insight into human biology and disease pathophysiology. In this thesis, we explored the methodological challenges facing these OMICs technologies and illustrated their applications in epidemiological studies. In part one, we focused on some of the methodological challenges facing OMICs research. These challenges included handling missing data in metabolomics, measurement agreement between high throughput proteomic measurements with standard clinical measurements, and challenges in developing prediction models using metabolomic data. The second part of this thesis addressed various epidemiological research questions by utilizing genomic data and metabolomics measurements (Metabolon and Nightingale platforms) and using advanced data analysis methods. These studies provided important insights into the associations between metabolites and hepatic triglyceride content, the associations of between the size of cytosine-adenine-guanine nucleotide repeats in the huntingtin gene with metabolomic profile, and the associations of the man-made per- and polyfluoroalkyl substances (PFAS) with metabolite levels. Show less
Cardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the... Show moreCardiovascular disease and diabetes are one of the leading causes of death worldwide. Multiple genetic and non-genetic factors play a role in this process. This dissertation aims to study the interplay between genetic factors and lifestyle factors (eg sleep, nutrition, physical activity) with diseases such as cardiovascular disease and risk factors for cardiovascular disease (diabetes). For example, 12 blood biomarkers associated with insulin resistance have been identified, 5 of which are specifically much higher in subjects with diabetes. In addition, it appeared that a short sleep duration and poor sleep quality are associated with poorer lipids in the blood (eg cholesterol and LDL) and more insulin resistance. With regard to sleep, 59 new genetic variants have also been identified with regard to blood lipids (HDL, LDL, triglycerides). In addition, the results indicate that a better lifestyle can also help reduce the development of new cardiovascular diseases in people with an increased genetic risk. This is particularly interesting to prevent diseases in persons at high risk. All in all, this thesis has provided new insights into the various factors that are potentially important in the development of cardiovascular disease and diabetes. Show less
In this thesis, we aimed to better understand how genetic variation affect the processes underlying health and disease, as trait-associated genetic variants are often located in non-coding... Show moreIn this thesis, we aimed to better understand how genetic variation affect the processes underlying health and disease, as trait-associated genetic variants are often located in non-coding regions. This hampers their interpretability, and has prompted the exploration of their effects on transcriptional regulation, a process that is crucial in the development of common and complex diseases. To do this, we have used a variety of omics data in a large collection of individuals from the general population. Using these data, we have investigated the local and distal effects of genetic variants on other molecular phenotypes, such as gene expression levels and DNA methylation levels of CpG sites, and the underlying mechanisms. This has resulted in a framework enabling the exploration of causal hypotheses about transcriptional regulation using genetics as a causal anchor. The approaches used in this thesis have yielded insight into transcriptional (dys)regulation and several underlying mechanisms. This will be helpful in better understanding how transcriptional regulation contributes to complex phenotypes related to health and disease, such as common diseases. Show less
In this thesis we reflect on the effects differential DNA binding of the estrogen receptor α (ERα) can have on the behavior of breast cancer and which factors can contribute to this. ERα is a... Show moreIn this thesis we reflect on the effects differential DNA binding of the estrogen receptor α (ERα) can have on the behavior of breast cancer and which factors can contribute to this. ERα is a transcription factor than can drive tumor cell proliferation and approximately 70% off all breast tumors is thought to be dependent on the activity of this hormone-mediated transcription factor. After stimulation of ERα a wild variety of co-factors are recruited, leading to the assembly of a transcriptional complex. Although there are multiple ways of targeting the action of ERα and thereby inhibiting tumor growth, still a significant proportion of patients develop a recurrence. Cross-resistance between the different endocrine therapy options can occur, but a proportion of patients that relapse on one type of therapy can still benefit from a different treatment modality, illustrating the existence of multiple resistance mechanisms which can be treatment selective. A better understanding of ERα-biology and the development of endocrine therapy resistance, can lead the way to the discovery of novel biomarkers and potential drug targets, that can further increase patient survival. Show less
In dit proefschrift worden de moleculaire mechanismen behandeld die onderliggend zijn aan artrose. Specifiek wordt genoomwijd onderzocht welke genen anders tot expressie komen in aangedaan... Show moreIn dit proefschrift worden de moleculaire mechanismen behandeld die onderliggend zijn aan artrose. Specifiek wordt genoomwijd onderzocht welke genen anders tot expressie komen in aangedaan vergeleken met gezond kraakbeen van artrose patienten. Dit in de context van epigenetische regulatie van gen expressie, specifiek door DNA methylatie in het licht van de lokale genetische context in de vorm van puntmutaties. Show less
