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 antigen (HLA) associations. These associations, however, are not universal and a number of genes outside the major histocompatibility complex may also play a role in susceptibility to type 1 AIH. Prime candidates at present are 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 polymorphic sites in the interleukin‐10 (IL‐10) gene promoter (positions −1082, −819, and −592), and 2 polymorphisms in the tumor necrosis factor‐α (TNF‐α) promoter (positions −308 and −238) in type 1 AIH. The study was performed on 2 independently collected DNA banks, each with appropriate controls, and throughout the analysis associations described in the first set were confirmed in the second set. Standard polymerase chain reaction (PCR)‐based genotyping techniques were used. Overall there were no significant differences in the distributions of the IL‐1B and IL‐10 alleles, genotypes, or haplotypes 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 patients, Pc = .014 and second set: 26% vs. 56%, P = .00008). However, TNF2 is found in strong linkage disequilibrium with the HLA A1‐B8‐DR3 haplotype and stratification analysis indicates that the association with TNF*2 is interdependent with HLA DRB10301 This is an indication that there is more than one susceptibility allele for type 1 AIH on chromosome 6p21.3.

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