Functional genomic analysis of genetic susceptibility loci for coronary artery disease

Coronary artery disease is now the leading cause of mortality in both developed and developing countries. While we have good treatments that target cholesterol metabolism, we believe that many other important causes of the disease are under-explored and not used as treatment targets. Recent genome-wide association studies have led to exciting discoveries of entirely novel susceptibility loci for coronary artery disease. Our Oxford-based collaboration, linking my group with that of Professor Martin Farrall and with Professor Rory Collins and colleagues at the CTSU, has had a leading role in these analyses. This includes the PROCARDIS Study and the C4D Genetics Consortium, and now the CardiogramPlusC4D Consortium (see references). We have invested substantial effort in collecting the patient samples and genetic data that have now taken us to the point where we are ready to start unravelling these susceptibility loci.

These large-scale projects generate important opportunities for statistical and bioinformatics analysis and for students with such computational interests there will be other suitable projects (see, in particular, Professor Farrall’s projects).

The focus of this proposed studentship is downstream, functional analysis which will aim to identify the causal gene(s) at a given locus and to investigate the impact of genetic manipulation of that gene in a relevant cell or experimental model. We will not seek to recapitulate the subtle genetic effects of the susceptibility SNPs themselves, but rather to find the roles of the relevant genes by knockdown (siRNA) or knockout (using either existing targeted ES lines or CRISPR technology). Depending on the interests of the candidate and the precise direction taken, this work will likely be co-supervised by senior colleagues whose research groups are expert either in atherosclerosis biology (Professor Keith Channon) or high throughput screening in cellular assays (Professor Shoumo Bhattacharya and Dr Ayman Al Haj Zen).