Refinement of the MHC risk map in a scandinavian primary sclerosing cholangitis population

Sigrid Næss; Benedicte A Lie; Espen Melum; Marita Olsson; Johannes R Hov; Peter J P Croucher; Jochen Hampe; Erik Thorsby; Annika Bergquist; James A Traherne; Erik Schrumpf; Kirsten Muri Boberg; Stefan Schreiber; Andre Franke; Tom H Karlsen

doi:10.1371/journal.pone.0114486

Refinement of the MHC risk map in a scandinavian primary sclerosing cholangitis population

PLoS One. 2014 Dec 18;9(12):e114486. doi: 10.1371/journal.pone.0114486. eCollection 2014.

Authors

Affiliations

¹ Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
² Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Department of Medical Genetics, University of Oslo and Oslo University Hospital, Oslo, Norway.
³ Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; K.G Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁴ Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden.
⁵ Department of Environmental Science, Policy, and Management, University of California Berkeley, Berkeley, California, United States of America.
⁶ First Medical Department, University Hospital Dresden, Technical University Dresden, Dresden, Germany.
⁷ Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Department of Immunology, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
⁸ Department of Gastroenterology and Hepatology, Karolinska Institutet, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
⁹ Division of Immunology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom; Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
¹⁰ Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
¹¹ Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Section for Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
¹² Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany; Department of General Internal Medicine, Christian-Albrechts-University, Kiel, Germany.
¹³ Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
¹⁴ Norwegian PSC Research Center, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; K.G Jebsen Inflammation Research Centre, Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Section for Gastroenterology, Department of Transplantation Medicine, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.

Abstract

Background: Genetic variants within the major histocompatibility complex (MHC) represent the strongest genetic susceptibility factors for primary sclerosing cholangitis (PSC). Identifying the causal variants within this genetic complex represents a major challenge due to strong linkage disequilibrium and an overall high physical density of candidate variants. We aimed to refine the MHC association in a geographically restricted PSC patient panel.

Methodology/principal findings: A total of 365 PSC cases and 368 healthy controls of Scandinavian ancestry were included in the study. We incorporated data from HLA typing (HLA-A, -B, -C, -DRB3, -DRB1, -DQB1) and single nucleotide polymorphisms across the MHC (n = 18,644; genotyped and imputed) alongside previously suggested PSC risk determinants in the MHC, i.e. amino acid variation of DRβ, a MICA microsatellite polymorphism and HLA-C and HLA-B according to their ligand properties for killer immunoglobulin-like receptors. Breakdowns of the association signal by unconditional and conditional logistic regression analyses demarcated multiple PSC associated MHC haplotypes, and for eight of these classical HLA class I and II alleles represented the strongest association. A novel independent risk locus was detected near NOTCH4 in the HLA class III region, tagged by rs116212904 (odds ratio [95% confidence interval] = 2.32 [1.80, 3.00], P = 1.35×10-11).

Conclusions/significance: Our study shows that classical HLA class I and II alleles, predominantly at HLA-B and HLA-DRB1, are the main risk factors for PSC in the MHC. In addition, the present assessments demonstrated for the first time an association near NOTCH4 in the HLA class III region.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Case-Control Studies
Cholangitis, Sclerosing / genetics*
HLA-B Antigens / genetics*
HLA-DRB1 Chains / genetics*
Humans
Polymorphism, Single Nucleotide*
Proto-Oncogene Proteins / genetics
Receptor, Notch4
Receptors, Notch / genetics
Scandinavian and Nordic Countries

Substances

HLA-B Antigens
HLA-DRB1 Chains
NOTCH4 protein, human
Proto-Oncogene Proteins
Receptor, Notch4
Receptors, Notch

Grants and funding

The study received support from the Norwegian PSC research center, the Research Computing Services at the University of Oslo and the DFG Excellence Cluster "Inflammation at Interfaces". Grant support was also received from the EU Seventh Framework Programme (FP7/2007-2013, grant number 262055, ESGI). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.