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In addition to the HLA-locus, six genetic risk factors for primary biliary cirrhosis (PBC) have been identified in recent genome-wide association studies (GWAS). To identify additional loci, we carried out a GWAS using 1,840 cases from the UK PBC Consortium and 5,163 UK population controls as part of the Wellcome Trust Case Control Consortium 3 (WTCCC3). Twenty-eight loci were followed up in an additional UK cohort of 620 PBC cases and 2,514 population controls. We identified 12 novel risk loci (P<5×10−8) and replicated all previously associated loci. Three further novel loci were identified by meta-analysis of data from our study and previously published GWAS results. New candidate genes include STAT4, DENND1B, CD80, IL7R, CXCR5, TNFRSF1A, CLEC16A, and NFKB1. This study has considerably expanded our knowledge of the genetic architecture of PBC.

; and the members of the UK-PBC Consortium*The biochemical response to ursodeoxycholic acid (UDCA)-so-called "treatment response"-strongly predicts long-term outcome in primary biliary cholangitis (PBC). Several long-term prognostic models based solely on the treatment response have been developed that are widely used to risk stratify PBC patients and guide their management. However, they do not take other prognostic variables into account, such as the stage of the liver disease. We sought to improve existing long-term prognostic models of PBC using data from the UK-PBC Research Cohort. We performed Cox's proportional hazards regression analysis of diverse explanatory variables in a derivation cohort of 1,916 UDCA-treated participants. We used nonautomatic backward selection to derive the best-fitting Cox model, from which we derived a multivariable fractional polynomial model. We combined linear predictors and baseline survivor functions in equations to score the risk of a liver transplant or liver-related death occurring within 5, 10, or 15 years. We validated these risk scores in an independent cohort of 1,249 UDCA-treated participants. The best-fitting model consisted of the baseline albumin and platelet count, as well as the bilirubin, transaminases, and alkaline phosphatase, after 12 months of UDCA. In the validation cohort, the 5-, 10-, and 15-year risk scores were highly accurate (areas under the curve: >0.90). Conclusions: The prognosis of PBC patients can be accurately evaluated using the UK-PBC risk scores. They may be used to identify high-risk patients for closer monitoring and second-line therapies, as well as low-risk patients who could potentially be followed up in primary care. (HEPATOLOGY 2016;63:930-950) SEE EDITORIAL ON PAGE 697 P rimary biliary cholangitis (PBC) is a chronic liver disease in which autoimmune destruction of the intrahepatic bile ducts results in cholestasis and progressive fibrosis.(1) Biliary injury may eventually lead to cirrhosis and liver failure-but the rate of disease progression is variable.(2) Across the spectrum, some patients with PBC progress to end-stage liver disease (ESLD) within a few years of diagnosis; some develop cirrhosis that remains well compensated; others (perhaps the majority) do not even develop cirrhosis. In PBC, as in other conditions, accurate prognostication enables management of the disease to be tailored to the patient. This is the basis of precision medicine-and it has clear benefits: patients at higherAbbreviations: AIH, autoimmune hepatitis; ALP, alkaline phosphatase; ALP12, alkaline phosphatase after 12 months of UDCA; AMA, anti-mitochondrial antibody; ANA, anti-nuclear antibodies; ALT, alanine aminotransferase; ALT12, ALT after 12 months of UDCA; AST, aspartate transaminase; AST12, AST after 12 months of UDCA; AUC, area under receiver operating characteristic curve; BIL, bilirubin; BIL12, bilirubin after 12 months of UDCA; CI, confidence interval; CRFs, case record forms; EASL, European Association for the Study of Liver; ESLD, end-stag...