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  • Review Article
  • Published:

Genetics of primary sclerosing cholangitis and pathophysiological implications

This article has been updated

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

Abstract

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.

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Figure 1: The principle aspects of bile duct lesions in PSC.
Figure 2: PSC visualized by cholangioscopy.
Figure 3: Genetic architecture of PSC and other complex diseases.
Figure 4: The gut–liver relationship in PSC.
Figure 5: Genetic correlation between PSC and Crohn's disease or ulcerative colitis.
Figure 6: A coeliac disease model of HLA-associated susceptibility in PSC and autoimmunity.
Figure 7: Crosstalk between immune cells, stromal cells and cholangiocytes.

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Change history

  • 30 March 2017

    In the version of this article initially published online, a line in the legend of Figure 3 and an attribution in the Acknowledgements were incorrect. The errors have been corrected for the print, HTML and PDF versions of the article.

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Acknowledgements

The authors are grateful to V. Paulsen for providing the cholangioscopy pictures for Fig. 2, and thank L. M. Sollid for providing the concept for Fig. 6. The authors thank all members of the International PSC Study Group (www.ipscsg.org) for their invaluable support and friendship throughout all the genetic studies in primary sclerosing cholangitis.

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Correspondence to Tom H. Karlsen.

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Candidate genes within table 1. (PDF 140 kb)

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Candidate genes within table 2 (PDF 142 kb)

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Jiang, X., Karlsen, T. Genetics of primary sclerosing cholangitis and pathophysiological implications. Nat Rev Gastroenterol Hepatol 14, 279–295 (2017). https://doi.org/10.1038/nrgastro.2016.154

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