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Gut 2001;49:288-294 ( August )

Article

Association of the tumour necrosis factor alpha  -308 but not the interleukin 10 -627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis S A Mitchella, J Grovec, A Spurklandd, K M Boberge, K A Flemingb, C P Dayc, E Schrumpfe, R W Chapmana, and the European Study Group of Primary Sclerosing Cholangitis

a Department of Gastroenterology, Oxford Radcliffe Hospital, Oxford, UK, b Nuffield Department of Pathology and Bacteriology, University of Oxford, Oxford, UK, c Centre for Liver Research, University of Newcastle, Newcastle upon Tyne, UK, d Institute of Transplant Immunology, National Hospital, Oslo, Norway, e Department of Medicine, National Hospital, Oslo, Norway

Correspondence to: Dr R Chapman.roger.chapman{at}ndm.ox.ac.uk

Accepted for publication 12 February 2001

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 alpha  (TNF-alpha ) 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-alpha and IL-10 promoter genes, respectively, and susceptibility to PSC.
METHODS---TNF-alpha -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 v ORcombined data =3.41, pcorr=10-4, respectively).
CONCLUSIONS---This study identified a significant association between possession of the TNF2 allele, a Gright-arrowA substitution at position -308 in the TNF-alpha 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.


Keywords: primary sclerosing cholangitis; tumour necrosis factor; interleukin 10; genetic polymorphism

© 2001 by Gut


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