The tumor necrosis factor-alpha promoter correlates with progression of primary biliary cirrhosis

Background/Aims: There have been many studies attempting to identify genes that determine susceptibility to primary biliary cirrhosis (PBC), but few s tudies have attempted to define the genes that modulate the natural history of the disease, There is a biallelic polymorphism, coined TNF1 and TNF2, i n the TNF alpha promoter region at -308, We investigated the relative frequ ency of the TNF1 and TNF2 alleles in patients with PBC, based on the hypoth esis that a polymorphism of the TNF alpha promoter region may be associated with the rate of progression and prognosis of PBC, Methods: Seventy-one Caucasoid patients with PBC and 133 healthy and unrela ted Caucasoid individuals mere studied. Genomic DNA was extracted from bloo d, and the mutation at position -308 of the TNF alpha gene analyzed by PCR and NcoI digestion. Results: Tn 71 patients with PBC, 56/71 (78.9%) patients were TNF1/TNF1 hom ozygotes, 14/71 (19.7%) were TNF1/TNF2 heterozygotes and 1/71 (1.4%) were T NF2/TNF2 homozygotes, In 133 healthy individuals, 109/133 (80.5%) patients were TNF1/TNF1 homozygotes, 24/133 (18%) were TNF1/TNF2 heterozygotes. No c ontrol individuals were TNF2/TNF2 homozygotes, The difference between the t wo groups was not statistically significant (p=0.3684). However, in patient s with TNF1/TNF1 the Mayo score for disease severity was 4.596+/-0.157 (mea n+/-SEM), compared to 5.637+/-0.420 for patients with TNF1/TNF2, This Mayo score was significantly higher in patients with the TNF1/TNF2 genotype than those with TNF1/TNF1 (p=0.0140), with an odds ratio of 4.9. Conclusions: Our data demonstrate that the presence of the TNF2 allele may be associated with a higher Mayo score, and thus with patients in a more ad vanced clinical stage. These data have both theoretical and clinical implic ations.