Association of STAT4 Polymorphisms with Susceptibility to Type-1 Autoimmune Hepatitis in the Japanese Population

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.

Diagnosis and Management of Autoimmune Hepatitis in Adults and Children: 2019 Practice Guidance and Guidelines From the American Association for the Study of Liver Diseases

“…AIH also has non-HLA genetic associations, but the odds ratios (ORs) for risk of AIH are far lower than those for HLA alleles. Susceptibility for AIH has been associated with genetic polymorphisms encoding cytotoxic T lymphocyte antigen-4 (CTLA-4), (33) tumor necrosis factor-alpha (TNF-α), (34,35) Fas (cluster of differentiation 95 [CD95] or apoptosis antigen-1), (36,37) vitamin D receptor, (38,39) signal transducer and activator of transcription 4, (40) transforming growth factor-beta 1, (41) macrophage migration inhibitory factor, (42) SH2B adapter protein 3, (43) caspase recruitment domain family member 10, (43) and the interleukin-23 (IL-23) receptor. (44) Dysfunctional products of genetic variants or deficient levels of gene product may disrupt homeostatic mechanisms that affect the proliferation and survival of autoreactive T and B cells, regulate cytokine production, and modulate inflammatory and immune responses.…”

Transitioning from Idiopathic to Explainable Autoimmune Hepatitis

“…Fas variant [86,87] Tumor necrosis factor-a (TNFA*2) [88] Vitamin D receptor [91,92] STAT4 variants [93] Transforming growth factor-b 1 [94] Cytokine genes (diverse) [95] May influence clinical phenotype [87] Alters immune responses [31,83,104] Lacks disease specificity [98] Often in non-liver immune diseases [101] May affect disease severity [87] Varies between patients [96][97][98][99] Unclear and controversial roles [96][97][98][99] Numbers in brackets are references AIH autoimmune hepatitis, ANA antinuclear antibodies, CARD10 caspase recruitment domain family member 10 gene, CTLA-4 cytotoxic T lymphocyte antigen-4 gene, CYP2D6 cytochrome mono-oxygenase P450 2D6, LC1 liver cytosol type 1, LMK1 liver kidney microsome type 1, pANCA perinuclear anti-neutrophil cytoplasmic antibodies, SH2B3 Scr homology 2 adaptor protein 3 gene, SMA smooth muscle antibodies, STAT4 signal transducer and activator of transcription 4…”

“…Polymorphisms outside the MHC have also been associated with autoimmune hepatitis [83], and they have included polymorphisms of the cytotoxic T lymphocyte antigen-4 gene (CTLA-4) [84,85], Fas gene (tumor necrosis factor receptor superfamily [TNFRSF] gene) [86,87], tumor necrosis factor-a (TNFA*2) gene [88][89][90], vitamin D receptor (VDR) gene [91,92], signal transducer and activator of transcription 4 (STAT4) gene [93], transforming growth factor beta 1 (TGF-b1) gene [94], and genes of various cytokines [95]. These polymorphisms have not been implicated in all ethnic populations of autoimmune hepatitis [96][97][98][99][100], and they have not been disease specific [101].…”

Review article: next‐generation transformative advances in the pathogenesis and management of autoimmune hepatitis

“…The pre‐study hypothesis can also affect the number of comparisons analysed in the study and the statistical validity of the associations. The association between the rs7574865 allele of the signal transducer and activator of transcription ( STAT ) gene and autoimmune hepatitis in Japanese patients ( P = .001) might be difficult to demonstrate if the loci had not been pre‐selected …”