The effects of the interactions of STAT4 rs7574865 with HBV mutations on the risk of hepatocellular carcinoma.

Signal transducer and activator of transcription 4 (STAT4) is closely related to liver diseases and affects the processes of inflammation and carcinogenesis by regulating immune responses. A single-nucleotide polymorphism rs7574865 (T > G) in STAT4 has been reported to be associated with the risk of hepatocellular carcinoma (HCC). In addition, hepatitis B virus (HBV) mutations are crucial risk factors for HBV-induced HCC. However, the effects of the interactions of STAT4 rs7574865 with HBV mutations on the risk of HCC remain unknown. Rs7574865 was genotyped in 846 healthy controls (HCs), 968 chronic hepatitis B (CHB) subjects, 316 liver cirrhosis (LC) subjects and 1021 HCC subjects using Sequenom MassArray. HBV mutations were detected via direct sequencing. Multivariate logistic regression analysis was used to evaluate the effects of the interactions of STAT4 rs7574865 with HBV mutations on the risk of HCC. We found that the rs7574865 TT genotype was significantly associated with HBeAg seroconversion (TT vs. GG, p = 0.012; TT vs. GT, p = 0.033). The rs7574865 GG genotype was significantly associated with increased risks of CHB (p = 0.048), LC (p = 0.005) and HCC (p < 0.001). The interaction term between rs7574865 and HBV C1913A significantly increased the risk of progression from CHB to HCC (p = 0.038), while the interaction term between rs7574865 and HBV T1674C significantly increased the risk of progression from LC to HCC (p = 0.023). STAT4 rs7574865 is significantly associated with the risks of CHB, LC and HCC. The interactions of rs7574865 with HBV C1913A and T1674C mutations significantly increase the risk of HCC, which have the potential to identify HBV-infected individuals who tend to progress from CHB or LC to HCC.