Association of the tumour necrosis factor alpha -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 cho lestatic liver disease of unknown aetiology. Abnormalities in immune regula tion and genetic associations suggest that PSC is an immune mediated diseas e. Several polymorphisms within the tumour necrosis factor a (TNF-alpha) an d interleukin 10 (IL-10) promoter genes have been described which influence expression of these cytokines. This study examines the possible associatio n 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 reactio n (PCR) in 160 PSC patients from Norway and the UK compared with 145 ethnic ally matched controls. IL-10 -627 genotypes were studied by FCR in 90 PSC p atients compared with 84 ethnically matched controls. Results - A total of 16% of Norwegian PSC patients and 12% of British PSC patients were homozygo us 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 (ORco mbined 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 in dependent of the presence of concurrent inflammatory bowel disease (IBD) in the PSC patients; 61% of PSC patients without IBD had TNF2 compared with 3 0% of controls (ORcombined data = 3.2 (95% CI 1.2-9.0); p(corr) = 0.006). T here 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 sus ceptibility 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 posse ssion 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 t he association of PSC with the A1-E8-DRB1*0301-DQA1*0501-DQB1*0201 haplotyp e. No association was found between the IL-10 -627 promoter polymorphism an d PSC.