Abstract
Background/AimsRecent studies demonstrated an association of STAT4 polymorphisms with autoimmune diseases including systemic lupus erythematosus and rheumatoid arthritis, indicating multiple autoimmune diseases share common susceptibility genes. We therefore investigated the influence of STAT4 polymorphisms on the susceptibility and phenotype of type-1 autoimmune hepatitis in a Japanese National Hospital Organization (NHO) AIH multicenter cohort study.Methodology/Principal FindingsGenomic DNA from 460 individuals of Japanese origin including 230 patients with type-1 autoimmune hepatitis and 230 healthy controls was analyzed for two single nucleotide polymorphisms in the STAT4 gene (rs7574865, rs7582694). The STAT4 rs7574865T allele conferred risk for type-1 autoimmune hepatitis (OR = 1.61, 95% CI = 1.23–2.11; P = 0.001), and patients without accompanying autoimmune diseases exhibited an association with the rs7574865T allele (OR = 1.50, 95%CI = 1.13–1.99; P = 0.005). Detailed genotype-phenotype analysis of type-1 autoimmune hepatitis patients with (n = 44) or without liver cirrhosis (n = 186) demonstrated that rs7574865 was not associated with the development of liver cirrhosis and phenotype (biochemical data and the presence of auto-antibodies).Conclusions/SignificanceThis is the first study to show a positive association between a STAT4 polymorphism and type-1 autoimmune hepatitis, suggesting that autoimmune hepatitis shares a gene commonly associated with risk for other autoimmune diseases.
Highlights
Autoimmune hepatitis (AIH) is characterized by chronic inflammation of the liver, interface hepatitis, hypergammaglobulinemia and production of autoantibodies [1,2]
Baseline data at entry Of the original 240 patients registered in the National Hospital Organization (NHO)-AIH study, 10 were excluded from analysis because of overlapping primary biliary cirrhosis (PBC)
Some patients with lower serum aminotransferase or total bilirubin were managed with ursodeoxycholic acid (UDCA) therapy alone, which was demonstrated to be efficacious in Japanese patients with type I autoimmune hepatitis [26]
Summary
Autoimmune hepatitis (AIH) is characterized by chronic inflammation of the liver, interface hepatitis, hypergammaglobulinemia and production of autoantibodies [1,2]. STAT4 has been confirmed in several studies and is clearly associated with autoimmune diseases such as RA or systemic lupus erythematosus (SLE) [8,9,10]. STAT4, a signal transducer and activator of transcription 4, is expressed in activated peripheral blood monocytes, dendritic cells and macrophages at the sites of inflammation in humans [11]. It is activated by interleukin (IL)-12, leading to T helper (Th) 1 and Th 17 differentiation, monocyte activation and interferon (IFN)-a production [12]. Since Th1 and Th17 cells have the capacity to cause autoimmunity [13], STAT4 may play a crucial role in the development of autoimmune diseases, including AIH
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