Functional characterisation of CYP2C9 variants of uncertain significance (360G-Wellcome-222538_Z_21_Z)

The liver is the main site for the elimination of medicines taken by people (a process termed drug metabolism). There are many enzymes involved in drug metabolism – one of these is cytochrome P450 2C9 (CYP2C9). CYP2C9 metabolises approximately 13% of all clinically used medications. One example is warfarin [1]. The activity of CYP2C9 varies between individuals which can affect drug efficacy and increase the likelihood for adverse drug reactions [2–4]. This is due to several factors including concurrent disease and the intake of other medications. Genetic factors also affect the activity of CYP2C9 – these are termed genetic polymorphisms. The function (i.e. whether they increase or decrease activity of CYP2C9) of almost half of these polymorphisms is not well-defined [5]. Preliminary work performed in the Pirmohamed lab has identified 16 high impact (e.g. frameshifts), 159 moderate impact (e.g. missense variants) and more than 8000 non-coding variants. The key goals of the project are: \- Correlate genetic variation in CYP2C9 to clinical outcomes using the UK BioBank, 100K Genomes Project and a well-characterised warfarin cohort \- Assess the effect of genetic variants on metabolomic parameters \- Prioritise variants for in vitro functional studies using CRISPR-Cas9, with effects on metabolism evaluated using LC-MS