title: The tumor necrosis factor-alpha promoter correlates with progression of primary biliary cirrhosis.
abstract: OBJECTIVE
  There have been many studies attempting to identify genes that determine susceptibility to primary biliary cirrhosis (PBC), but few studies have attempted to define the genes that modulate the natural history of the disease. There is a biallelic polymorphism, coined TNF1 and TNF2, in the TNFalpha promoter region at -308. We investigated the relative frequency of the TNF1 and TNF2 alleles in patients with PBC, based on the hypothesis that a polymorphism of the TNFalpha 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 unrelated Caucasoid individuals were studied. Genomic DNA was extracted from blood, and the mutation at position -308 of the TNFalpha gene analyzed by PCR and NcoI digestion.
  
  
  RESULTS
  In 71 patients with PBC, 56/71 (78.9%) patients were TNF1/TNF1 homozygotes, 14/71 (19.7%) were TNF1/TNF2 heterozygotes and 1/71 (1.4%) were TNF2/TNF2 homozygotes. In 133 healthy individuals, 109/133 (80.5%) patients were TNF1/TNF1 homozygotes, 24/133 (18%) were TNF1/TNF2 heterozygotes. No control individuals were TNF2/TNF2 homozygotes. The difference between the two groups was not statistically significant (p = 0.3684). However, in patients with TNF1/TNF1 the Mayo score for disease severity was 4.596+/-0.157 (mean +/- 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 advanced clinical stage. These data have both theoretical and clinical implications.
authors.affiliation: Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis, 95616-8660, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tanaka
authors.forename: S
authors.initials: S
authors.lastname: Quaranta
authors.forename: A
authors.initials: A
authors.lastname: Mattalia
authors.forename: R
authors.initials: R
authors.lastname: Coppel
authors.forename: F
authors.initials: F
authors.lastname: Rosina
authors.forename: M
authors.initials: M
authors.lastname: Manns
authors.forename: M E
authors.initials: ME
authors.lastname: Gershwin
mesh_terms: D000483:Alleles; D002140:California; D004247:DNA / Q000097:blood; D018450:Disease Progression; D006580:Genetic Carrier Screening; D005838:Genotype; D005858:Germany; D006720:Homozygote; D006801:Humans; D007558:Italy; D008105:Liver Cirrhosis, Biliary / Q000235:genetics* / Q000503:physiopathology*; D016017:Odds Ratio; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D011401:Promoter Regions, Genetic; D012016:Reference Values; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics*; D014739:Victoria; D044465:White People
chemical_list: D014409:Tumor Necrosis Factor-alpha; D004247:DNA