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

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 a (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 FCR 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); 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 (ORcombined 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 (ORcombined data = 3.8, p(corr) = 10(-6) v O-Rcombined data = 3.2) p(corr) = 10(-5) v ORcombined 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-a promoter, and susceptibility to PSC. This association was secondary to the association of PSC with the A1-E8-DRB1*0301-DQA1*0501-DQB1*0201 haplotype. No association was found between the IL-10 -627 promoter polymorphism and PSC.