Frequency and nature of cytokine gene polymorphisms in type 1 autoimmune hepatitis

Genetic involvement in type 1 autoimmune hepatitis (AIH) is indicated by a marked female preponderance and strong, well-established, human leukocyte a ntigen (HLA) associations. These associations, however, are not universal a nd a number of genes outside the major histocompatibility complex may also play a role in susceptibility to type 1 AIH, Prime candidates at present ar e those polymorphic genes encoding the proinflammatory and immunoregulatory cytokines, The aim of this study was to investigate, for the first time, 2 members of the interleukin-1 (IL-1) family (IL-1B and IL-1RN), 3 polymorph ic sites in the interleukin-10 (IL-10) gene promoter (positions -1082, -819 , and -592), and 2 polymorphisms in the tumor necrosis factor-alpha (TNF-al pha) promoter (positions -308 and -238) in type 1 AIH, The study was perfor med on 2 independently collected DNA banks, each with appropriate controls, and throughout the analysis associations described in the first set were c onfirmed in the second set. Standard polymerase chain reaction (PCR)-based genotyping techniques were used. Overall there were no significant differen ces in the distributions of the IL-1B and IL-10 alleles, genotypes, or hapl otypes in either study set. In contrast we report a significant association between type 1 AIH and TNF*2 (first set: 34% of controls vs. 49% of patien ts, Pc =.014 and second set: 26% vs. 56%, P =.00008). However, TNF*2 is fou nd in strong linkage disequilibrium with the HLA A1-B8-DR3 haplotype and st ratification analysis indicates that the association with TNF*2 is interdep endent with HLA DRB1*0301. This is an indication that there is more than on e susceptibility allele for type 1 AIH on chromosome 6p21.3.