Genetics of primary sclerosing cholangitis and pathophysiological implications

• Published in: Nature reviews. Gastroenterology & hepatology Vol. 14; no. 5; pp. 279 - 295
• Main Authors: Jiang, Xiaojun, Karlsen, Tom H.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2017; Nature Publishing Group
• Subjects: 631/208/1516; 692/4020/1503/1581/257; 692/4020/4021/1607/2744; 692/699/249/1313; Biomedicine; Cholangitis, Sclerosing - genetics; Cholangitis, Sclerosing - physiopathology; Gastroenterology; Genetic Predisposition to Disease; Hepatology; Humans; Medicine & Public Health; review-article
• ISSN: 1759-5045; 1759-5053
• DOI: 10.1038/nrgastro.2016.154

Key Points Primary sclerosing cholangitis (PSC) is a complex genetic disease of the bile ducts and the bowel, in which multiple genetic and environmental factors interact in causing inflammation and fibrosis 22 susceptibility loci for PSC have been established at a genome-wide significance level ( P ≤5 × 10 −8 ), with the HLA complex representing the strongest finding by several orders of magnitude The overall genetic architecture of PSC resembles that of prototypical autoimmune diseases, with some genetic overlap also being evident for IBD susceptibility genes Genetic findings in PSC so far explain <10% of disease liability, and specific environmental risk factors probably account for >50% of the unexplained fraction Individual gene findings should be interpreted with an emphasis on tissue-specific and PSC-specific functions, and published studies performed before the knowledge of a PSC association might not be relevant The pool of susceptibility genes serves a major resource for translational studies aimed at deciphering pathophysiology in PSC, and could guide developments in the direction of effective treatments Results from genetic studies of primary sclerosing cholangitis have identified a number of risk loci associated with the disease. Here, Jiang and Karlsen comprehensively discuss the identity and function of risk genes, the potential roles they have in pathogenesis and future research efforts. Primary sclerosing cholangitis (PSC) is a chronic disease leading to fibrotic scarring of the intrahepatic and extrahepatic bile ducts, causing considerable morbidity and mortality via the development of cholestatic liver cirrhosis, concurrent IBD and a high risk of bile duct cancer. Expectations have been high that genetic studies would determine key factors in PSC pathogenesis to support the development of effective medical therapies. Through the application of genome-wide association studies, a large number of disease susceptibility genes have been identified. The overall genetic architecture of PSC shares features with both autoimmune diseases and IBD. Strong human leukocyte antigen gene associations, along with several susceptibility genes that are critically involved in T-cell function, support the involvement of adaptive immune responses in disease pathogenesis, and position PSC as an autoimmune disease. In this Review, we survey the developments that have led to these gene discoveries. We also elaborate relevant interpretations of individual gene findings in the context of established disease models in PSC, and propose relevant translational research efforts to pursue novel insights.