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Small duct primary sclerosing cholangitis without inflammatory bowel disease is genetically different from large duct disease

Authors

  • Sigrid Næss,

    1. Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    2. Institute of Clinical Medicine, University of Oslo, Oslo, Norway
    3. Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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  • Einar Björnsson,

    1. Division of Gastroenterology and Hepatology, Department of Internal Medicine, Landspitali University Hospital, Reykjavik, Iceland
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  • Jarl A. Anmarkrud,

    1. Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    2. Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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  • Said Al Mamari,

    1. Transitional Gastroenterology Unit, Oxford University Hospitals, Oxford, UK
    2. Liver Unit, Sultan Qaboos Hospital, Salalah, Oman
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  • Brian D. Juran,

    1. Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN, USA
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  • Konstantinos N. Lazaridis,

    1. Division of Gastroenterology and Hepatology, Center for Basic Research in Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN, USA
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  • Roger Chapman,

    1. Department of Hepatology, John Radcliffe University Hospitals NHS Trust, Oxford, UK
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  • Annika Bergquist,

    1. Department of Gastroenterology and Hepatology, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
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  • Espen Melum,

    1. Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    2. Institute of Clinical Medicine, University of Oslo, Oslo, Norway
    3. Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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  • Steven G. E. Marsh,

    1. Anthony Nolan Research Institute and UCL Cancer Institute, Royal Free Hospital, London, UK
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  • Erik Schrumpf,

    1. Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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  • Benedicte A. Lie,

    1. Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    2. Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway
    3. K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
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  • Kirsten M. Boberg,

    1. Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    2. Institute of Clinical Medicine, University of Oslo, Oslo, Norway
    3. Section for Gastroenterology, Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
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  • Tom H. Karlsen,

    1. Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    2. Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    3. K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
    4. Division of Gastroenterology, Department of Clinical Medicine, University of Bergen, Bergen, Norway
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  • Johannes R. Hov

    Corresponding author
    1. Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    2. Institute of Clinical Medicine, University of Oslo, Oslo, Norway
    3. Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    4. K.G. Jebsen Inflammation Research Centre, Institute of Clinical Medicine, University of Oslo, Oslo, Norway
    5. Section for Gastroenterology, Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway
    • Correspondence

      Johannes R. Hov, MD, PhD

      Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Postboks 4950 Nydalen, Oslo N-0424, Norway

      Tel: +47 23 07 3627

      Fax: +47 23 07 3928

      e-mail: j.e.r.hov@medisin.uio.no

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Abstract

Background & Aims

Small duct primary sclerosing cholangitis (PSC) is phenotypically a mild version of large duct PSC, but it is unknown whether these phenotypes share aetiology. We aimed to characterize their relationship by investigating genetic associations in the human leucocyte antigen (HLA) complex, which represent the strongest genetic risk factors in large duct PSC.

Methods

Four classical HLA loci (HLA-A, HLA-B, HLA-C and HLA-DRB1) were genotyped in 87 small duct PSC patients, 485 large duct PSC patients and 1117 controls across three geographical regions.

Results

HLA-DRB1*13:01 (OR = 2.0, 95% CI 1.2–3.4, P = 0.01) and HLA-B*08 (OR = 1.6, 95% CI 1.1–2.4, P = 0.02) were significantly associated with small duct PSC compared with healthy controls. Based on the observed frequency of HLA-B*08 in small duct PSC, the strongest risk factor in large duct PSC, an estimated 32% (95% CI 4–65%) of this population can be hypothesized to represent early stages or mild variants of large duct PSC. This subgroup may be constituted by small duct PSC patients with inflammatory bowel disease (IBD), which greatly resembled large duct PSC in its HLA association. In contrast, small duct PSC without IBD was only associated with HLA-DRB1*13:01(P = 0.03) and was otherwise distinctly dissimilar from large duct PSC.

Conclusions

Small duct PSC with IBD resembles large duct PSC in its HLA association and may represent early stages or mild variants of large duct disease. Different HLA associations in small duct PSC without IBD could indicate that this subgroup is a different entity. HLA-DRB1*13:01 may represent a specific risk factor for inflammatory bile duct disease.

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