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  • Association of the tumour necrosis factor α −308 but not the interleukin 10 −627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis

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Liver disease
Association of the tumour necrosis factor α −308 but not the interleukin 10 −627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis
  1. S A Mitchella,
  2. J Grovec,
  3. A Spurklandd,
  4. K M Boberge,
  5. K A Flemingb,
  6. C P Dayc,
  7. E Schrumpfe,
  8. R W Chapmana,
  9. the European Study Group of Primary Sclerosing Cholangitis
  1. aDepartment of Gastroenterology, Oxford Radcliffe Hospital, Oxford, UK, bNuffield Department of Pathology and Bacteriology, University of Oxford, Oxford, UK, cCentre for Liver Research, University of Newcastle, Newcastle upon Tyne, UK, dInstitute of Transplant Immunology, National Hospital, Oslo, Norway, eDepartment of Medicine, National Hospital, Oslo, Norway
  1. Dr RChapman.roger.chapman{at}ndm.ox.ac.uk

Abstract

BACKGROUND AND AIMS Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown aetiology. Abnormalities in immune regulation and genetic associations suggest that PSC is an immune mediated disease. Several polymorphisms within the tumour necrosis factor α (TNF-α) and interleukin 10 (IL-10) promoter genes have been described which influence expression of these cytokines. This study examines the possible association between polymorphisms at the −308 and −627 positions in the TNF-α and IL-10 promoter genes, respectively, and susceptibility to PSC.

METHODS TNF-α −308 genotypes were studied by polymerase chain reaction (PCR) in 160 PSC patients from Norway and the UK compared with 145 ethnically matched controls. IL-10 −627 genotypes were studied by PCR in 90 PSC patients compared with 84 ethnically matched controls.

RESULTS A total of 16% of Norwegian PSC patients and 12% of British PSC patients were homozygous for the TNF2 allele compared with 3% and 6% of respective controls. The TNF2 allele was present in 60% of PSC patients versus 30% of controls (ORcombined data=3.2 (95% confidence intervals (CI) 1.8–4.5); pcorr=10−5). The association between the TNF2 allele and susceptibility to PSC was independent of the presence of concurrent inflammatory bowel disease (IBD) in the PSC patients; 61% of PSC patients without IBD had TNF2 compared with 30% of controls (ORcombined data=3.2 (95% CI 1.2–9.0); pcorr=0.006 ). There was no difference in the −627 IL-10 polymorphism distributions between patients and controls in either population. The increase in TNF2 allele in PSC patients only occurs in the presence of DRB1*0301 (DR3) and B8. In the combined population data, DRB1*0301 showed a stronger association with susceptibility to PSC than both the TNF2 and B8 alleles (ORcombined data=3.8, pcorr=10−6 v ORcombined data=3.2, pcorr=10−5 vORcombined data =3.41, pcorr=10−4, respectively).

CONCLUSIONS This study identified a significant association between possession of the TNF2 allele, a G→A substitution at position −308 in the TNF-α promoter, and susceptibility to PSC. This association was secondary to the association of PSC with the A1-B8-DRB1*0301-DQA1*0501-DQB1*0201 haplotype. No association was found between the IL-10 −627 promoter polymorphism and PSC.

  • primary sclerosing cholangitis
  • tumour necrosis factor
  • interleukin 10
  • genetic polymorphism

  • Abbreviations used in this paper

    PSC
    primary sclerosing cholangitis
    IL-10
    interleukin 10
    TNF-α
    tumour necrosis factor α
    IBD
    inflammatory bowel disease
    PCR
    polymerase chain reaction
    OR
    odds ratio
    PBC
    primary biliary cirrhosis

    • https://doi.org/10.1136/gut.49.2.288

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    • Abbreviations used in this paper

      PSC
      primary sclerosing cholangitis
      IL-10
      interleukin 10
      TNF-α
      tumour necrosis factor α
      IBD
      inflammatory bowel disease
      PCR
      polymerase chain reaction
      OR
      odds ratio
      PBC
      primary biliary cirrhosis
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