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http://hdl.handle.net/11375/27426
Title: | Exploring the Role of Biomarker Genetics in Cardiovascular Disease |
Authors: | Sjaarda, Jennifer |
Advisor: | Pare, Guillaume |
Department: | Medical Sciences |
Publication Date: | Dec-2018 |
Abstract: | Biomarkers provide the opportunity to identify subclinical disease states before development of the disease and apply preventative measures, facilitate research and understanding of disease mechanisms, and allow for the assessment of therapeutic measures. However, a major challenge in the field of biomarker research is to discern cause and effect, and as a result, association has often been mistaken for causation. Additionally, the pathogenesis behind chronic diseases is extremely complex, resulting from several modifiable and unmodifiable risk factors and often caused by an interaction of many biomarkers simultaneously. Furthermore, biomarker levels show marked differences across ethnicities and it is difficult to distinguish whether this is a result of environmental or genetic factors. Through longitudinal, genetic, multi-biomarker studies, these barriers can be partially overcome. This thesis addresses how advancements in genetic and biomarker research may help to gain novel insights into both known and novel biomarkers of cardiovascular disease, inform and guide clinical decision-making and validate potential disease target pathways. Using a variety of statistical approaches, we analyzed 4,147 participants of the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial measured for 237 biomarkers and followed for an average of 6.2 years, to investigate the genetic effects on biomarkers and their relation to cardiovascular diseases. Specifically, we applied Mendelian randomization (MR) analyses to identify novel, causal mediators of coronary artery disease (CAD) and chronic kidney disease (CKD). Additionally, we used admixture mapping to explore the impact of ancestry on serum biomarker levels in the Native Latin ORIGIN population and identified genes conferring differential risk across ancestries. We identified macrophage colony-stimulating factor 1 (CSF1) and stromal cell-derived factor (CXCL12) as novel, causal mediators of CAD using MR. Similarly, MR analysis also revealed uromodulin (UMOD) and human EGF receptor 2 (HER2) as new mediators of CKD. Through admixture mapping, we have demonstrated the importance of ethnicity across a comprehensive panel of biomarkers and shown a novel method for inferring the contribution of ethnicity to phenotypic traits in admixed individuals. By applying two major statistical methods employed in genetic epidemiology we have revealed important insights into the role of biomarkers in health and disease. Taken together, this thesis implicates new biomarkers for CAD and CKD which are potential therapeutic interventions for prevention and treatment. Furthermore, this work indicates the importance of ancestry in disease, and paves the way for clinical treatment which is tailored to ethnicity. Future studies may adopt the novel approaches presented here to identify additional causal markers of disease and biological pathways and processes which are influenced by ancestry. |
URI: | http://hdl.handle.net/11375/27426 |
Appears in Collections: | Open Access Dissertations and Theses |
Files in This Item:
File | Description | Size | Format | |
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Sjaarda_Jennifer_L_2019January_PhD.pdf | 5.89 MB | Adobe PDF | View/Open |
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