Exploring liver disease cause & effect through Mendelian randomisation.
Principal Investigator: Dr Constantinos Parisinos
Approved Research ID: 31037
Approval date: August 1st 2017
Non-alcoholic fatty liver disease (NAFLD) describes the build-up of fat in the liver. One in three people in the UK have NAFLD, which in time may progress to liver scarring (NASH) and failure (cirrhosis). The liver has important roles in clotting, cholesterol metabolism and immunity; NAFLD and NASH have been linked to heart disease and cancer risk. By combining genetic, clinical and imaging data, we aim to: a) Identify factors that cause NAFLD and NASH. b) Investigate whether NAFLD and NASH cause other common diseases (e.g. heart disease, cancer). c) Identify drug targets for NASH. Individuals with non-alcoholic fatty liver disease and steatohepatitis (NAFLD/NASH) are at increased risk for other conditions including liver cirrhosis, cardiovascular disease, chronic kidney disease, diabetes, and certain cancers. Liver disease is the only common cause of mortality that is rising in incidence in the UK, and has been highlighted by the Chief Medical Officer as a public health priority. We aim to use genomic approaches to investigate: a) risk factors which cause liver fibrosis b) whether liver fibrosis is an independent risk factor for other non-communicable diseases and traits c) potential therapeutic targets for liver fibrosis. We will perform genome wide association studies (GWAS) on liver fibrosis scores (derived from MRI liver images) to investigate common mutations (variants) associated with NAFLD/NASH. This will allow us to create a genetic score for NAFLD/NASH. This genetic risk score is unaffected by disease and allocated at random (before birth, Mendelian randomisation), in the same way as treatment allocation in a clinical trial. When combined with other genetic scores and clinical outcomes it allows us to investigate: 1) Causal risk factors for NAFLD/NASH. 2) Whether NAFLD/NASH causes other diseases. 3) Potential drug targets for NAFLD/NASH. The full cohort will be included to maximise statistical power for genome wide association and Mendelian randomisation studies.