Small duct primary sclerosing cholangitis without inflammatory bowel disease is genetically different from large duct disease
Article first published online: 7 MAR 2014
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Volume 34, Issue 10, pages 1488–1495, November 2014
How to Cite
Liver Int. 2014; 34: 1488–1495
- Issue published online: 13 OCT 2014
- Article first published online: 7 MAR 2014
- Accepted manuscript online: 11 FEB 2014 06:14PM EST
- Manuscript Accepted: 4 FEB 2014
- Manuscript Received: 8 OCT 2013
- Norwegian PSC Research Center
- National Institute of Diabetes and Digestive and Kidney Diseases
- National Institute of Allergy and Infectious Diseases
- National Human Genome Research Institute
- National Institute of Child Health and Human Development
- Juvenile Diabetes Research Foundation International. Grant Number: U01 DK062418
- NIH. Grant Number: DK084960
- human leucocyte antigens;
- inflammatory bowel disease;
- large duct;
- primary sclerosing cholangitis;
- small duct
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.
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.
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.
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.