Shah, SH;
(2014)
Discovery and Application of Genetic Determinants of Cardiovascular Disease Risk Factors.
Doctoral thesis (PhD), UCL (University College London).
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Abstract
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
| Type: | Thesis (Doctoral) |
|---|---|
| Qualification: | PhD |
| Title: | Discovery and Application of Genetic Determinants of Cardiovascular Disease Risk Factors |
| Open access status: | An open access version is available from UCL Discovery |
| Language: | English |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science |
| URI: | https://discovery.ucl.ac.uk/id/eprint/1417181 |
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