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Primary biliary cirrhosis (PBC) is a classical autoimmune liver disease for which effective immunomodulatory therapy is lacking. Here we perform meta-analyses of discovery datasets from genome-wide association studies of European subjects (n=2,764 cases and 10,475 controls) followed by validation genotyping in an independent cohort (n=3,716 cases and 4261 controls). We discover and validate six previously unknown risk loci for PBC (Pcombined<5×10−8) and used pathway analysis to identify JAK-STAT/IL12/IL27 signaling and cytokine-cytokine pathways, for which relevant therapies exist.

Background: Many patients with primary biliary cirrhosis (PBC) are asymptomatic at the time of diagnosis. However, because most studies of asymptomatic PBC have been small and from tertiary centres, asymptomatic PBC remains poorly characterised. Aims: To describe the features and progression of initially asymptomatic PBC patients. Methods: Follow up by interview and note review of a large geographically and temporally defined cohort of patients with PBC, collected by multiple methods. Results: Of a total of 770 patients, 469 (61%) were asymptomatic at diagnosis. These patients had biochemically and histologically less advanced disease than initially symptomatic patients. Median survival was similar in both groups (9.6 v 8.0 years, respectively) possibly due to excess of non-liver related deaths in asymptomatic patients (31% v 57% of deaths related to liver disease). Survival in initially asymptomatic patients was not affected by subsequent symptom development. By the end of follow up, 20% of initially asymptomatic patients had died of liver disease or required liver transplantation. The majority of initially asymptomatic patients developed symptoms of liver disease if they were followed up for long enough (Kaplan-Meier estimate of proportion developing symptoms: 50% after five years, 95% after 20 years). However, 45% of patients remained asymptomatic at the time of death. Conclusions: Although asymptomatic PBC is less severe at diagnosis than symptomatic disease, it is not associated with a better prognosis, possibly due to an increase in non-hepatic deaths. The reasons for this are unclear but may reflect confounding by other risk factors or surveillance bias. These findings have important implications for future treatment strategies.

There is a widespread impression that the number of patients with the autoimmune liver disease primary biliary cirrhosis (PBC) is increasing, although its incidence and prevalence vary widely. Using thorough case-finding methods and rigorous definitions to assess changes in incidence and prevalence with time and to explore the symptomatology and mortality of the disease in a large group of unselected patients, we performed a descriptive epidemiological study of PBC in a well defined population over a fixed period of time using