title: Small duct primary sclerosing cholangitis without inflammatory bowel disease is genetically different from large duct disease.
abstract: OBJECTIVE
  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.
authors: Division of Cancer Medicine, Surgery and Transplantation, Department of Transplantation Medicine, Norwegian PSC Research Center, Oslo University Hospital, Rikshospitalet, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, Oslo, Norway; Research Institute of Internal Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway.
authors: Sigrid
authors: S
authors: Naess
authors: Einar
authors: E
authors: Björnsson
authors: Jarl A
authors: JA
authors: Anmarkrud
authors: Said
authors: S
authors: Al Mamari
authors: Brian D
authors: BD
authors: Juran
authors: Konstantinos N
authors: KN
authors: Lazaridis
authors: Roger
authors: R
authors: Chapman
authors: Annika
authors: A
authors: Bergquist
authors: Espen
authors: E
authors: Melum
authors: Steven G E
authors: SG
authors: Marsh
authors: Erik
authors: E
authors: Schrumpf
authors: Benedicte A
authors: BA
authors: Lie
authors: Kirsten M
authors: KM
authors: Boberg
authors: Tom H
authors: TH
authors: Karlsen
authors: Johannes R
authors: JR
authors: Hov
mesh_terms: D015209:Cholangitis, Sclerosing / Q000145:classification* / Q000235:genetics*; D005838:Genotype; D015795:HLA-B8 Antigen / Q000235:genetics*; D059811:HLA-DRB1 Chains / Q000235:genetics*; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000235:genetics; D015810:Linkage Disequilibrium; D009664:Norway; D016017:Odds Ratio; D010641:Phenotype; D012307:Risk Factors; D013548:Sweden; D006113:United Kingdom; D014481:United States
chemical_list: D015795:HLA-B8 Antigen; D059811:HLA-DRB1 Chains; C492962:HLA-DRB1*13:01 antigen
keywords: human leucocyte antigens; inflammatory bowel disease; large duct; primary sclerosing cholangitis; small duct