AimsTo investigate the impact of signal transducer and activator of transcription 4 (STAT4) and the protein tyrosine phosphatase N22 (PTPN22) gene single nucleotide polymorphisms (SNPs), gene–gene interactions and haplotype on type-1 Autoimmune Hepatitis (AIH) risk.ResultsLogistic regression analysis showed that type 1 AIH was significantly higher in carriers of T allele of rs7574865 than those with GG genotype (P- value less than 0.001), higher in carriers of C allele of rs7582694 than those with GG genotype (P- value < 0.001), and lower in carriers of T allele of rs2476601 than those with CC genotype (P- value < 0.001). GMDR model indicated a significant two-locus model (p = 0.0100) involving rs7582694 and rs2476601. Participants with GC or CC of rs7582694 and CC of rs2476601 genotype have the highest type 1 AIH risk (P- value < 0.001), after covariates adjustment. Haplotype containing the rs7582694-C and rs7574865-T alleles were associated with a statistically increased type 1 AIH risk (P < 0.001).Materials and MethodsLogistic regression was performed to investigate association between SNPs within STAT4 and PTPN22 gene and susceptibility to type 1 AIH. Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combinations among the 4 SNPs.ConclusionsWe conclude that rs7574865 and rs7582694 in STAT4 gene minor alleles, interaction between rs7582694 and rs2476601, and haplotype containing the rs7582694-C and rs7574865-T alleles are associated with increased type 1 AIH risk, but rs2476601 in PTPN22 gene minor allele is associated with decreased type 1 AIH risk.