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Epithelial-mesenchymal transition (EMT) plays an important role in the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We hypothesized that germline variants in the major EMT regulatory genes ( SNAIL1 ,  ZEB1 ,  ZEB2 ,  TWIST1 ) may influence the development of HBV-related HCC. We included 421 cases of HBsAg-positive patients with HCC, 1371 cases of HBsAg-positive subjects without HCC [patients with chronic hepatitis B (CHB) or liver cirrhosis (LC)] and 618 cases of healthy controls in the case-control study. Genotype, allele, and haplotype associations in the major EMT regulatory genes were tested. Environment-gene and gene-gene interactions were analysed using the non-parametric model-free multifactor dimensionality reduction (MDR) method. The  SNAIL1 rs4647958T>C was associated with a significantly increased risk of both HCC (CT+CC  vs . TT:  OR =1.559; 95% confidence interval [ CI ], 1.073-2.264;  P =0.020) and CHB+LC (CT+CC  vs . TT:  OR =1.509; 95%  CI , 1.145-1.988;  P =0.003). Carriers of the  TWIST1 rs2285681G>C (genotypes CT+CC) had an increased risk of HCC (CG+CC  vs . GG:  OR =1.407; 95%  CI , 1.065-1.858;  P =0.016). The  ZEB2 rs3806475T>C was associated with significantly increased risk of both HCC ( P   recessive  =0.001) and CHB+LC ( P   recessive <0.001). The CG haplotype of the rs4647958/rs1543442 haplotype block was associated with significant differences between healthy subjects and HCC patients ( P =0.0347). Meanwhile, the CT haplotype of the rs2285681/rs2285682 haplotype block was associated with significant differences between CHB+LC and HCC patients ( P =0.0123). In MDR analysis, the combination of  TWIST1 rs2285681,  ZEB2 rs3806475,  SNAIL1 rs4647958 exhibited the most significant association with CHB+LC and Health control in the three-locus model. Our results suggest significant single-gene associations and environment-gene/gene-gene interactions of EMT-related genes with HBV-related HCC.

Germline Variants and Genetic Interactions of Several EMT Regulatory Genes Increase the Risk of HBV-Related Hepatocellular Carcinoma