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Title: Discovery and application of genetic determinants of cardiovascular disease risk factors
Author: Shah, S. H.
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 2014
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The focus of my PhD has been two-­‐fold: First, to improve the understanding of the biology behind a well-­‐known cardiovascular disease (CVD) risk factor -­‐ left ventricular mass, by identifying novel genetic loci associated with this risk factor. A large-­‐scale association meta-­‐analysis in over 10,000 individuals identified four novel loci associated with electrocardiographically-­‐determined left ventricular mass. Second, to explore the application of known genetic determinants of the main blood lipid fractions, the latter being well-­‐known CVD risk factors and therapeutic targets. I assess the use of genetic variants associated with total cholesterol, low-­‐ density lipoprotein-­‐cholesterol (LDL-­‐C), high-­‐density lipoprotein-­‐cholesterol (HDL-­‐C) and triglycerides for discriminating healthy individuals from those that have a high absolute risk of CVD, those that require lipid-­‐lowering medication, and those that have a coronary event. The lipid genetic variants showed poor discriminatory ability for all three outcomes and provided no improvement over the widely-­‐used, non-­‐ genetic Framingham 10 year CVD risk score. Lipid-­‐associated genetic variants were also used to generate genetic risk score instruments for LDL-­‐C, HDL-­‐C and triglycerides, which were applied in a Mendelian randomisation analysis to determine their causal relationship with carotid-­‐intima media thickness (CIMT). CIMT has been a widely used surrogate outcome measure in clinical trials of CVD drugs. LDL-­‐C-­‐lowering drugs have shown to reduce CIMT progression and CHD risk in clinical trials. However, the extent of any causal association between HDL-­‐C or triglycerides and CIMT is unclear. The results from this MR analysis support a casual relationship with LDL-­‐C, but not with HDL-­‐C and triglycerides, which may indicate that CIMT is a less useful surrogate end point in clinical trials of primarily HDL-­‐C or triglyceride modifying therapies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available