Abstract

Previous studies have found that the polymorphisms of tumor necrosis factor-α induced protein 3 (TNFAIP3) were associated with several autoimmune diseases. However, the role of TNFAIP3 polymorphisms in type-1 autoimmune hepatitis (AIH-1) remained unclear. The present study aimed to clarify the association of TNFAIP3 polymorphisms with AIH-1 risk in a Chinese Han population. The TaqMan SNP genotyping assay was used to determine the distribution of TNFAIP3 polymorphisms in 432 AIH-1 patients and 500 healthy controls. The association of TNFAIP3 polymorphisms and clinical characteristic was further evaluated. Five TNFAIP3 polymorphisms (rs2230926, rs5029939, rs10499194, rs6920220, rs582757) were analyzed in the present study. No significant association could be observed between rs2230926, rs5029939, rs6920220, rs582757 and the susceptibility to AIH-1 in Chinese Han population. Compared with wild-type genotype CC at rs10499194, individuals carrying CT genotype had a significantly increased risk for developing AIH-1 (OR = 2.32, 95%CI 1.44–3.74). Under a dominant model, CT/TT carriers have a 140% increased risk of AIH-1 than CC carriers (OR = 2.40, 95%CI 1.50–3.87). The rs10499194 T allele was also found to be significantly associated with AIH-1 risk (OR = 2.41, 95%CI 1.51–3.82). In addition, higher serum ALT, AST levels and more common cirrhosis were observed in AIH-1 patients with T allele (CT/TT) than those with CC genotype. In conclusion, TNFAIP3 rs10499194 T allele and CT genotype were associated with an increased risk for AIH-1, suggesting rs10499194 polymorphism as a candidate of susceptibility locus to AIH-1.

Highlights

  • Among all Autoimmune hepatitis (AIH)-1 patients, 310 (71.7%) were positive for antinuclear antibodies (ANA) (>1:40) and 138 (31.9%) for ASMA and 46 (10.6%) for both. 72 (16.6%) AIH-1 patients had liver cirrhosis at the time of diagnosis. 312 (72.2%) patients were diagnosed with definite AIH, and 120 (27.8%) with probable AIH. 66 AIH-1 patients were accompanied with other immune diseases including 42 thyroid disease, 14 inflammatory bowel disease and 10 rheumatic disease

  • Genes located within the human leukocyte antigens (HLA) region may play a dominant role in the predisposition to AIH-1, HLA alone could not account for the entire genetic predisposition, because

  • Previous studies have found susceptibility to AIH-1 may result from genetic variation in immune mechanisms involved in establishing and maintaining self-tolerance, such as cytotoxic T lymphocyte antigen–4 gene (CTLA-4), TNF-a, Fas, etc [22, 23]

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Summary

Introduction

Genetic studies looking outside HLA genes have discovered the polymorphisms of cytotoxic T lymphocyte antigen–4 gene (CTLA-4), tumor necrosis factor–α gene (TNF-α) and Fas as potential non-HLA susceptibility gene to AIH-1[8, 9]. Previous study demonstrated defects in A20 expression were associated with the development of several human autoimmune disorders [12]. The previous study identified A20-mediated control of dendritic cells activation as a vital checkpoint in the development of systemic autoimmunity[15]. Studies have shown that TNFAIP3 genetic polymorphisms were associated with susceptibility to multiple human autoimmune and inflammatory diseases including rheumatoid arthritis (RA), systemic lupus erythematous (SLE), polymyositis/dermatomyositis and inflammatory bowel diseases (IBDs)[16,17,18,19]. To determine the effect of TNFAIP3 polymorphisms on AIH-1 risk in Chinese Han population, we performed this case-control study and evaluate the potential associations between five TNFAIP3 polymorphisms (rs2230926, rs5029939, rs10499194, rs6920220, rs582757) with AIH-1

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