Primary sclerosing cholangitis (PSC) is a progressive chronic cholestatic liver disease, affecting young males predominantly. It causes stricturing of the intrahepatic and extrahepatic bile ducts, often leading to biliary cirrhosis, with an increased risk of colorectal and hepato-biliary malignancy. It is commonly associated with inflammatory bowel disease (IBD). Specific medical therapy is ineffective and for patients who develop end-stage liver disease, liver transplantation remains the only definitive treatment option.

The UK PSC study was set up in 2008 to recruit patients with PSC, to collect clinical data and DNA samples, to study phenotypic characteristics and the role of genetic risk factors in PSC. To date, more than 2,000 patients have been recruited from UK hospitals, making it the largest independent PSC cohort worldwide.

I studied the phenotypic characteristics of the cohort and identified an increased risk of requiring liver transplantation in patients with both intrahepatic and extrahepatic bile duct disease, in comparison to those with disease limited to intrahepatic ducts. Further study of the clinical and laboratory parameters, helped develop a UK PSC risk score, which allowed risk stratification of patients with PSC at the time of diagnosis.

I performed a replication/candidate gene study followed by a genome wide association study in a cohort of 1,030 and 1,020 patients respectively with 5,162 controls. Genome-wide signficant association was identified at two novel loci: 10p15 and 12q24, containing candidate genes Il2RA and SH2B3/ATXN2 respectively. These genes have important roles in adaptive immune pathways, implicating an immue mediated disease process in the pathogenesis of PSC. As part of UK PSC, I also contributed to two large scale genome wide association studies in an international collaboration, which identified 13 novel loci associated with PSC.

The UK PSC cohort is a unique national resource of patients with PSC and further deep phenotyping and quality of life studies are planned, in addition to undertaking clinical trials for novel therapeutic agents. The study of phenotypic characteristics and genetic association, undertaken in patients with PSC are described in this thesis.