An integrated genetic and proteomic approach to understanding cardiovascular disease aetiology

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My research programme is focussed on using genomic technologies to understand the links between inflammation and cardiovascular disease. Despite advances in prevention and treatment, cardiovascular disease is the leading cause of death worldwide, highlighting the need for new therapeutic strategies. Most deaths are due to myocardial infarction or "heart attack". Heart attacks occur when fatty deposits in the wall of an artery rupture, triggering formation of a clot which blocks the blood supply to the heart. These fatty deposits build up over many years in a process called atherosclerosis. Traditionally atherosclerosis was thought to be solely due to build-up of excess fats, but over the last few decades the importance of inflammation in this process has been increasingly recognised. Inflammation usually occurs as a protective response to infection or injury, but in certain circumstances it can be harmful. A large number of drugs have been developed to treat harmful inflammation in autoimmune diseases such as rheumatoid arthritis. This raises the possibility that these or similar treatments could be effective in cardiovascular disease. Indeed, the recent CANTOS trial showed that canakinumab, a drug (originally designed for rheumatic diseases) which targets the IL1-beta protein, reduced coronary events in patients with high inflammation levels. There are multiple proteins involved in inflammation and so the challenge is identifying those that are the most promising drug targets.I propose to address this by integrating 'high-dimensional' genetic and proteomic data. As a result of advances in technology, it now possible to simultaneously measure large numbers of proteins (the 'proteome') in the blood in large numbers of individuals. However, simply showing an association of a protein with cardiovascular disease does not necessarily indicate that the protein is a valid drug target, as correlation does not always reflect causation. To circumvent this issue, I will integrate genetic information, utilising an approach called 'Mendelian randomisation'. This method takes advantage of the randomisation of genetic variants that occurs during reproduction, providing in effect a natural randomised trial. The first step is to identify genetic variants that affect the level of a particular protein. Then, by examining whether individuals who inherit such genetic variants are at higher or lower risk of cardiovascular disease, we can establish whether that protein is likely plays a causal role in disease and thus whether it is a valid drug target.In a complementary strand of work in collaboration with Prof. Justin Mason (Imperial College London), I am studying patients with Takayasu arteritis, a rare disease characterised by arterial inflammation, which often results in vascular narrowing, or, less commonly, dilatation (aneurysm). Cardiovascular complications are a major cause of morbidity. The prognosis in Takayasu arteritis is very variable - some patients have a benign course, while others develop progressive vascular injury. We will examine the plasma proteome to understand factors that influence this variability and to identify signatures that could be used to distinguish high-risk patients in need of stronger immunosuppressive treatment from those in whom milder, less toxic treatments would be sufficient. In addition, we anticipate that improved understanding of an extreme form of vascular inflammation should provide insights into cardiovascular disease more generally.