Graduate Research Prize Winners 2008
My first degree was at Monash University in Australia and I came to Oxford on a Commonwealth Scholarship to read for a D.Phil. in medical statistics at the Clinical Trial Service Unit and Epidemiological Studies Unit (CTSU), supervised by Dr Sarah Parish and Professor Rory Collins.
In Oxford, my thesis has focused on the design, analysis and interpretation of a genome-wide association study of statin-induced myopathy. Large-scale randomised evidence shows that statin therapy reduces the incidence of heart attacks, strokes and revascularisation procedures by about one-fifth per 1mmol/L LDL-cholesterol reduction, and it is estimated that over 30 million people worldwide are now taking statins. However, rarely statins can damage muscles causing pain, weakness or even muscle breakdown with release of myoglobin leading to the risk of renal failure and death. The incidence of this myopathy is typically only about one per 10,000 patients per year or less with standard doses of the drugs (for example, 20-40mg simvastatin daily), but it increases with higher doses and with concomitant use of certain drugs, such as cyclosporine, which can inhibit statin metabolism.
The genome-wide association study typed over 318,000 genetic markers (plus additional fine-mapping) in 85 subjects with definite or incipient myopathy and 90 controls, all of whom were taking 80 mg of simvastatin daily as part of a CTSU co-ordinated trial involving 12,000 participants. Together with my colleagues who were co-ordinating the trial and undertaking the genotyping, I discovered that one genomic region containing the SLCO1B1 gene was associated with myopathy. I then confirmed this finding in another large trial of 40 mg of simvastatin daily involving 20,000 participants. The number of copies of one particular variant, the rs4149056 C allele, accounted for up to 60% of the myopathy risk. The importance of these results is that they will lead to more effective and safer treatment of individuals at risk of cardiovascular disease.
During my D.Phil, I have benefited from close collaboration with colleagues in the CTSU and at the Wellcome Trust for Human Genetics nearby and also from opportunities to present findings at academic conferences in the USA and in Ireland. I have been inspired by the intriguing CTSU and University seminar series, and by the opportunity to talk to so many world-renowned speakers, particularly at Green College. In my spare time I have also enjoyed being President of Green College student body, horse-riding, dancing and rowing.
Following my studies, I am going to continue as a medical statistician within CTSU, investigating statin-induced myopathy in different populations and broadening my experience in other areas of CTSU's expertise, such as large clinical trials, meta-analyses and observational studies in coronary heart disease.
- Link E, Parish S, Armitage J, Bowman L, Heath S, Matsuda F, Gut I, Lathrop M, and Collins R. (2008) The SEARCH Collaborative Group. "SLCO1B1 variants and statin-induced myopathy -a genome wide study" N. Engl. J. Med. 359:789-799.
Estimated Cumulative Risk of Myopathy Associated with Taking 80 mg of Simvastatin Daily According to SLCO1B1 rs4149056 Genotype.