UCL Discovery
UCL home » Library Services » Electronic resources » UCL Discovery

Discovery and Application of Genetic Determinants of Cardiovascular Disease Risk Factors

Shah, SH; (2014) Discovery and Application of Genetic Determinants of Cardiovascular Disease Risk Factors. Doctoral thesis (PhD), UCL (University College London). Green open access

[thumbnail of SoniaShah_PhDThesis_Final.pdf]
Preview
Text
SoniaShah_PhDThesis_Final.pdf

Download (16MB) | Preview

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
Downloads since deposit
66Downloads
Download activity - last month
Download activity - last 12 months
Downloads by country - last 12 months

Archive Staff Only

View Item View Item