Association of the tumour necrosis factor alpha -308 but not the interleukin 10 -627 promoter polymorphism with genetic susceptibility to primary sclerosing cholangitis.
OBJECTIVE
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 (OR(combined data)=3.2 (95% confidence intervals (CI) 1.8--4.5); p(corr)=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 (OR(combined data)=3.2 (95% CI 1.2--9.0); p(corr)=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 (OR(combined data)=3.8, p(corr)=10(-6) v OR(combined data)=3.2, p(corr)=10(-5) v OR(combined data )=3.41, p(corr)=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-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.
Mitchell
S A
SA
Department of Gastroenterology, Oxford Radcliffe Hospital, Oxford, UK.
Grove
J
J
Spurkland
A
A
Boberg
K M
KM
Fleming
K A
KA
Day
C P
CP
Schrumpf
E
E
Chapman
R W
RW
D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D015209:Cholangitis, Sclerosing / Q000150:complications / Q000235:genetics* / Q000276:immunology; D016001:Confidence Intervals; D005260:Female; D005838:Genotype; D006650:Histocompatibility Testing; D006720:Homozygote; D006801:Humans; D015212:Inflammatory Bowel Diseases / Q000150:complications / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*
D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10