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

Sigrid Næss, Einar Björnsson, Jarl A. Anmarkrud, Said Al Mamari, Brian D. Juran, Konstantinos N Lazaridis, Roger Chapman, Annika Bergquist, Espen Melum, Steven G E Marsh, Erik Schrumpf, Benedicte A. Lie, Kirsten M. Boberg, Tom H. Karlsen, Johannes R. Hov

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Pages (from-to)1488-1495
Number of pages8
JournalLiver International
Volume34
Issue number10
DOIs
StatePublished - Nov 1 2014

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Sclerosing Cholangitis
Inflammatory Bowel Diseases
HLA Antigens
Bile Duct Diseases

Keywords

  • Human leucocyte antigens
  • Inflammatory bowel disease
  • Large duct
  • Primary sclerosing cholangitis
  • Small duct

ASJC Scopus subject areas

  • Hepatology

Cite this

Small duct primary sclerosing cholangitis without inflammatory bowel disease is genetically different from large duct disease. / Næss, Sigrid; Björnsson, Einar; Anmarkrud, Jarl A.; Mamari, Said Al; Juran, Brian D.; Lazaridis, Konstantinos N; Chapman, Roger; Bergquist, Annika; Melum, Espen; Marsh, Steven G E; Schrumpf, Erik; Lie, Benedicte A.; Boberg, Kirsten M.; Karlsen, Tom H.; Hov, Johannes R.

In: Liver International, Vol. 34, No. 10, 01.11.2014, p. 1488-1495.

Research output: Contribution to journalArticle

Næss, S, Björnsson, E, Anmarkrud, JA, Mamari, SA, Juran, BD, Lazaridis, KN, Chapman, R, Bergquist, A, Melum, E, Marsh, SGE, Schrumpf, E, Lie, BA, Boberg, KM, Karlsen, TH & Hov, JR 2014, 'Small duct primary sclerosing cholangitis without inflammatory bowel disease is genetically different from large duct disease', Liver International, vol. 34, no. 10, pp. 1488-1495. https://doi.org/10.1111/liv.12492
Næss, Sigrid ; Björnsson, Einar ; Anmarkrud, Jarl A. ; Mamari, Said Al ; Juran, Brian D. ; Lazaridis, Konstantinos N ; Chapman, Roger ; Bergquist, Annika ; Melum, Espen ; Marsh, Steven G E ; Schrumpf, Erik ; Lie, Benedicte A. ; Boberg, Kirsten M. ; Karlsen, Tom H. ; Hov, Johannes R. / Small duct primary sclerosing cholangitis without inflammatory bowel disease is genetically different from large duct disease. In: Liver International. 2014 ; Vol. 34, No. 10. pp. 1488-1495.
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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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AU - Næss, Sigrid

AU - Björnsson, Einar

AU - Anmarkrud, Jarl A.

AU - Mamari, Said Al

AU - Juran, Brian D.

AU - Lazaridis, Konstantinos N

AU - Chapman, Roger

AU - Bergquist, Annika

AU - Melum, Espen

AU - Marsh, Steven G E

AU - Schrumpf, Erik

AU - Lie, Benedicte A.

AU - Boberg, Kirsten M.

AU - Karlsen, Tom H.

AU - Hov, Johannes R.

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N2 - 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.

AB - 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.

KW - Human leucocyte antigens

KW - Inflammatory bowel disease

KW - Large duct

KW - Primary sclerosing cholangitis

KW - Small duct

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