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The aims of our research project are to study the effect of genetic variation on 1) response to medication, 2) on the progression of cardiovascular and metabolic diseases in medicated patients, and 3) to use genetic variation in genes encoding drug targets or drug modulators to study possible effects of drugs. Mutation in genes encoding or modulating drug targets can be associated with clinical features similar to the effect of the drug and this can enable the identification of drug repurposing opportunities or the identification of possible adverse drug reaction. Identifying genetic determinants of drug response is a key step towards personalized medicine as it will allow clinicians to optimize treatment for individuals based on their genetic profile. The second objective of our project will help understand the genomic basis of metabolic and cardiovascular diseases, a leading global cause of death. Finally, our genomic approach to predict the effects of drugs could lead to the prediction of associated clinical outcomes. Such findings could eventually benefit patients by broadening the range of available drug treatments. To identify genetic determinants of drug response, we will assess the difference in disease incidence between genetic subgroups of individuals following pharmacotherapy for cardiovascular or metabolic diseases. For example, we could look at users of anti-diabetes drugs such as metformin and conduct genome-wide screens to identify genetic variants associated with reductions in HbA1c and disease severity such as retinopathy. We will also conduct phenome-wide scans for effects associated with mutations in drug target genes. This will be achieved by testing mutations between cardiovascular disease drug target genes and all available medical diagnostics reported in the UK Biobank. To maximize statistical power, the full cohort will be requested for this project.