American Journal of Gastroenterology ISSN 0002-9270 C  2005 by Am. Coll. of Gastroenterology doi: 10.1111/j.1572-0241.2005.41053.x Published by Blackwell Publishing Fas Polymorphisms Influence Susceptibility to Autoimmune Hepatitis Akira Hiraide, M.D., Ph.D., Fumio Imazeki, M.D., Ph.D., Osamu Yokosuka, M.D., Ph.D., Tatsuo Kanda, M.D., Ph.D., Hiroshige Kojima, M.D., Ph.D., Kenichi Fukai, M.D., Ph.D., Yoichi Suzuki, M.D., Ph.D., Akira Hata, M.D., Ph.D., and Hiromitsu Saisho, M.D., Ph.D. Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University; and Department of Public Health, Graduate School of Medicine, Chiba University, Chiba City, Japan BACKGROUND Genetic factors associated with autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), AND AIMS: immune-mediated chronic inflammatory liver diseases of unknown etiology, remain to be elucidated. Polymorphisms of the gene encoding Fas have been linked to a variety of autoimmune diseases. We hypothesized that Fas gene polymorphisms might be genetic markers for AIH and PBC. METHODS: To determine the frequency and significance of Fas polymorphisms in patients with AIH and PBC, 74 Japanese AIH patients, 98 Japanese PBC patients, and 132 ethnically matched control subjects were investigated by the use of the Taqman assay. RESULTS: We found significant differences between AIH patients and controls in allele frequencies of Fas-670 (p = 0.009), Fas IVS (intervening sequence) 2nt176 (p = 0.018), Fas IVS3nt46 (p = 0.031), and Fas IVS5nt82 (p = 0.013) polymorphisms. Haplotype analysis revealed that one of the haplotypes, GATGC, was associated with increased AIH prevalence. On the other hand, we found no statistically significant differences between PBC patients and controls in allele frequencies of the Fas polymorphisms genotyped in this study. CONCLUSIONS: These results indicate a genetic link of Fas polymorphisms to the development of AIH. Further studies are needed to determine the genetic factors contributing to the development of AIH. (Am J Gastroenterol 2005;100:1322–1329) INTRODUCTION Autoimmune hepatitis (AIH) is a hepatocellular inflamma- tion of unknown etiology characterized by elevated serum transaminase levels, liver-associated serum autoantibodies, hypergammaglobulinemia, histological signs of interface hepatitis and portal lymphocytic infiltration, and a response to immunosuppressive treatment (1, 2). Genetic factors appear to be involved in the pathogenesis of AIH. In previous studies, human leukocyte antigens (HLA) DRB1 ∗ 0301 and ∗ 0401 in Caucasoid and HLADR4 in Japanese have been identified as independent determinants of susceptibility to AIH (3–6). In addition, tumor necrosis factor-α (TNF-α) and complement C4 allele have been associated with AIH (4, 7–9). Polymor- phisms of cytotoxic T lymphocyte antigen 4 (CTLA4) and vitamin D receptor (VDR) have been reported as nonmajor histocompatibility complex (MHC) susceptibility determi- nants in AIH (10, 11). Primary biliary cirrhosis (PBC) is an autoimmune chronic cholestatic disease characterized serologically by antimito- chondrial antibodies (AMA), and histologically by immune- mediated damage to the biliary epithelial cells lining the small intrahepatic bile ducts (12). Similar genetic factors have been analyzed to elucidate genetic susceptibility to PBC. The ge- netic typing of HLA class II and III alleles revealed a highly significant increase of HLA DR8, C4B2, and C4AQ0 alle- les in patients with PBC compared with controls (13–18). In Japanese, PBC is also related to HLA DR8, specifically with the DRB1 ∗ 0803 allele (19, 20). Polymorphisms of the interleukin 1 (IL-1), CTLA4, and vitamin D receptor (VDR) genes have been reported as markers of PBC susceptibility (11, 21, 22). A number of genes outside the MHC locus may also play a role in the susceptibility to autoimmune liver diseases. One such candidate is the Fas gene. The Fas molecule is an apoptosis-signaling cell surface receptor belonging to the TNF receptor superfamily. Several studies have indicated that Fas may participate in autoimmune disease development such as systemic lupus erythematosus, primary Sjogren’s syn- drome, and multiple sclerosis (23–26). Thus, Fas might also be involved in the development of AIH and PBC. The human Fas gene has nine exons spanning 26 kilobases and maps to chromosome 10q24.1 (27–31). At least 20 distinct Fas polymorphisms have been reported in humans. Hence, in the present study, we chose 5 of these polymorphisms, which have been studied in those autoimmune diseases, including 1322