Inflammatory biomarker genomics

Inflammatory biomarkers are a group of proteins circulating in the blood that play key roles in inflammation. The blood levels of these biomarkers are partially genetically determined, and elevated levels are hallmarks for various types of diseases and sometimes even directly implicated in pathogenesis. In this thesis we aimed to identify previously unknown genetic regions (‘loci’) for well-known inflammatory biomarkers, to understand how they influence molecular levels, and whether they play a causal role in various diseases. First, I present three large-scale genome-wide association studies (GWASs) that led to the identification of new genetic loci for levels of four inflammatory biomarkers: TNF-α, Interleukin-6, serum albumin and total protein. These analyses were supported by a software pipeline that automated data quality checks for these studies. Furthermore, we focussed on disentangling the molecular mechanisms through which genetic determinants influence levels of one of the most widely clinically used inflammatory biomarkers, C-Reactive Protein, followed by an investigation of its involvement in multiple disease classes. The thesis concludes with a review on GWAS for Coronary Artery Disease, in which I argue that we can improve our understanding of the mechanisms by which genetic loci influence traits of interest through the integration with other layers of molecular data, an approach known as systems genetics. This research has increased our biological understanding of genetic determinants of inflammatory biomarkers and provides further leads for investigation of their direct involvement in the pathogenesis of disease.

Dissertation: http://hdl.handle.net/11370/facdf8b0-f8f0-4280-b4de-6052925f382c