Format

Send to

Choose Destination

See 1 citation found by title matching your search:

Gut. 2018 Aug;67(8):1517-1524. doi: 10.1136/gutjnl-2016-313598. Epub 2017 Aug 4.

Genetic association analysis identifies variants associated with disease progression in primary sclerosing cholangitis.

Author information

1
Department of Gastroenterology and Hepatology, University of Groningen and University Medical Centre Groningen, Groningen, The Netherlands.
2
Department of Gastroenterology and Hepatology, Academic Medical Center, Amsterdam, The Netherlands.
3
Norwich Medical School, Faculty of Medicine and Health Sciences, University of East Anglia, Norwich, UK.
4
Academic Department of Medical Genetics, University of Cambridge, Cambridge, UK.
5
Norwegian PSC Research Center, Division of Cancer Medicine, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
6
Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
7
Department of Surgery, Wellcome Trust-Medical Research Council Stem Cell Institute, Anne McLaren Laboratory, University of Cambridge, Cambridge, UK.
8
Department of Surgery, University of Cambridge and NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
9
Institute for Liver and Digestive Health, University College London, Royal Free Hospital, London, UK.
10
Department of Gastroenterology Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany.
11
Integrated Research and Treatment Center-Transplantation (IFB-tx) Hannover Medical School, Hannover, Germany.
12
Division of Gastroenterology and Hepatology, University of Alberta, Edmonton, Alberta, Canada.
13
Department of Medicine, Division of Hepatology, University of Cambridge, Cambridge, UK.
14
Department of Clinical Medicine, Division of Gastroenterology, Sapienza University of Rome, Rome, Italy.
15
Center for Digestive Diseases, Karolinska University Hospital, Karolinska Institutet, Stockholm, Sweden.
16
Department of Medicine Huddinge, Center for Infectious Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
17
Department of Internal Medicine, Division of Gastroenterology and Hepatology, Landspitali University Hospital, Reykjavik, Iceland.
18
K G Jebsen Inflammation Research Centre and Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
19
Division of Gastroenterology and Hepatology, University of California Davis, Davis, California, USA.
20
Sapienza University of Rome, Medico-Surgical Sciences and Biotechnologies, Rome, Italy.
21
Department of Medicine and Surgery, Program for Autoimmune Liver Diseases, International Center for Digestive Health, University of Milan-Bicocca, Milan, Italy.
22
Department of Hepatology, AP-HP, Hôpital Saint Antoine, Paris, France.
23
General Internal Medicine, University Health Network, Toronto General Hospital, Toronto, Canada.
24
Department of Medicine and Research Laboratory of Internal Medicine, Medical School, University of Thessaly, Larissa, Greece.
25
Division of Gastroenterology and Hepatology, Mayo Clinic Minnesota, Rochester, Minnesota, USA.
26
Department of Medicine, Snyder Institute of Chronic Diseases, University of Calgary, Calgary, Canada.
27
Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany.
28
Department of Medicine, Division of Gastroenterology, Helsinki University Hospital, Helsinki, Finland.
29
Department of Surgical Oncological and Gastroenterological Sciences, University of Padova, Padova, Italy.
30
Department of Surgery Oncology and Gastroenterology, University of Padova, Padova, Italy.
31
Department of Medicine, University Hospital of Heidelberg, Heidelberg, Germany.
32
Centre for Liver Research, NIHR Biomedical Research Unit, University of Birmingham, Birmingham, UK.
33
Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, The Netherlands.
34
Department of Medicine II, Liver Center Munich, University of Munich, Munich, Germany.
35
Popgen Biobank, University Hospital Schleswig-Holstein, Christian-Albrechts-University, Kiel, Germany.
36
Institute for Epidemiology, Christian-Albrechts University, Kiel, Germany.
37
Wellcome Trust Genome Campus, Wellcome Trust Sanger Institute, Cambridge, UK.
38
Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, Gothenburg, Sweden.
39
Department of Gastroenterology, Università Politecnica delle Marche, Ospedali Riuniti University Hospital, Ancona, Italy.
40
Liver and Internal Medicine Unit, Medical University of Warsaw, Warsaw, Poland.
41
Department of Internal Medicine Hepatology and Gastroenterology, Charité Universitätsmedizin Berlin, Campus Virchow Klinikum, Berlin, Germany.
42
Liver Unit Hospital Clinic, IDIBAPS, CIBERehd, University of Barcelona, Barcelona, Spain.
43
Department of Internal Medicine IV, University Hospital of Heidelberg, Heidelberg, Germany.
44
Department of Medicine I, Krankenhaus Barmherzige Brüder, Munich, Germany.
45
1st Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
46
Department for General Internal Medicine, Christian-Albrechts-University, Kiel, Germany.
47
Section of Gastroenterology, Department of Transplantation Medicine, Division of Cancer, Surgery and Transplantation, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
48
Inflammatory Bowel Disease (IBD) Group Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital Toronto, Ontario, Canada.
49
Department of Hepatobiliary Surgery and Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
50
1st Department of Medicine, University of Mainz, Mainz, Germany.
51
Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands.
52
Department of Internal Medicine, University of Thessaly, Larissa, Greece.
53
Department of Hepatology, John Radcliffe University Hospitals NHS Trust, Cambridge, UK.
#
Contributed equally

Abstract

OBJECTIVE:

Primary sclerosing cholangitis (PSC) is a genetically complex, inflammatory bile duct disease of largely unknown aetiology often leading to liver transplantation or death. Little is known about the genetic contribution to the severity and progression of PSC. The aim of this study is to identify genetic variants associated with PSC disease progression and development of complications.

DESIGN:

We collected standardised PSC subphenotypes in a large cohort of 3402 patients with PSC. After quality control, we combined 130 422 single nucleotide polymorphisms of all patients-obtained using the Illumina immunochip-with their disease subphenotypes. Using logistic regression and Cox proportional hazards models, we identified genetic variants associated with binary and time-to-event PSC subphenotypes.

RESULTS:

We identified genetic variant rs853974 to be associated with liver transplant-free survival (p=6.07×10-9). Kaplan-Meier survival analysis showed a 50.9% (95% CI 41.5% to 59.5%) transplant-free survival for homozygous AA allele carriers of rs853974 compared with 72.8% (95% CI 69.6% to 75.7%) for GG carriers at 10 years after PSC diagnosis. For the candidate gene in the region, RSPO3, we demonstrated expression in key liver-resident effector cells, such as human and murine cholangiocytes and human hepatic stellate cells.

CONCLUSION:

We present a large international PSC cohort, and report genetic loci associated with PSC disease progression. For liver transplant-free survival, we identified a genome-wide significant signal and demonstrated expression of the candidate gene RSPO3 in key liver-resident effector cells. This warrants further assessments of the role of this potential key PSC modifier gene.

KEYWORDS:

Primary sclerosing cholangitis; genetics; liver transplantation

PMID:
28779025
PMCID:
PMC5797498
DOI:
10.1136/gutjnl-2016-313598
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center