Personalised Medicine for Non-Alcoholic Fatty Liver Disease

Abstract

Non-Alcoholic Fatty Liver Disease (NAFLD) is a chronic and dangerous condition which has grown in prevalence over recent decades due to increasing rates of obesity, affecting roughly a quarter of adults globally. This thesis develops a useable NAFLD definition which can be applied to large retrospective data sets consisting of medical records for selected cohorts. The morbidity and mortality associated with NAFLD is investigated, especially related to extrahepatic cancer. This thesis also aims to identify genetic modifiers of NAFLD risk in Scottish and South Indian populations.

Data from three retrospective Scottish cohorts with electronic health records (EHRs) were analysed in the current thesis. These were the GoDARTS, SHARE and Tayside and Fife Diabetics cohorts. Genotypic data was available for a number of patients in GoDARTS and SHARE. Data from the Dr Mohan’s Diabetes Speciality Clinic (DMDSC) were also analysed, which consisted of clinical measurements from clinic visits, and genotypic data.

An accurate and practical NAFLD definition based on two raised ALT levels was developed, which had a sensitivity of 97.4% in the GoDARTS cohort. This definition was used for subsequent NAFLD analyses. Patients with NAFLD experienced significantly more hospital admissions, and earlier death than those without NAFLD. We found NAFLD is associated with increased risk of cancer incidence, and cancer death, which accounts for a large portion of the excess morbidity and mortality seen in NAFLD patients. GWAS analyses revealed that PNPLA3 rs738409 is a major genetic risk factor in both Scottish and South Indian populations. Candidate gene studies revealed variants associated with endothelin function and with GLP1 receptors had significant effects on NAFLD.

This thesis applies an accurate and novel NAFLD definition to retrospective cohorts with EHRs, and found increased morbidity and mortality in individuals with this phenotype. A large proportion of this is explained by increased cancer incidence and cancer death seen in these individuals. A number of genetic risk factors for NAFLD are described, including novel loci in endothelin and GLP1R related genes.

Date of Award	2021
Original language	English
Sponsors	AstraZeneca
Supervisor	Colin Palmer (Supervisor) & John Dillon (Supervisor)