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

Wen-Xuan Liu; Lei Yang; Hui-Min Yan; Li-Na Yan; Xiao-Lin Zhang; Ning Ma; Long-Mei Tang; Xia Gao; Dian-Wu Liu

doi:10.3389/fonc.2021.564477

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

Front Oncol. 2021 Jun 11:11:564477. doi: 10.3389/fonc.2021.564477. eCollection 2021.

Authors

Wen-Xuan Liu¹, Lei Yang¹, Hui-Min Yan², Li-Na Yan¹, Xiao-Lin Zhang¹, Ning Ma³, Long-Mei Tang¹, Xia Gao¹, Dian-Wu Liu¹

Affiliations

¹ Department of Epidemiology and Statistics & Hebei Province Key Laboratory of Environment and Human Health, School of Public Health, Hebei Medical University, Shijiazhuang, China.
² Department of Laboratory Medicine, Shijiazhuang Fifth Hospital, Shijiazhuang, China.
³ Department of Social Medicine and Health Care Management & Hebei Province Key Laboratory of Environment and Human Health, School of Public Health, Hebei Medical University, Shijiazhuang, China.

Abstract

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 SNAIL1rs4647958T>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 TWIST1rs2285681G>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 ZEB2rs3806475T>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 TWIST1rs2285681, ZEB2rs3806475, SNAIL1rs4647958 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.

Keywords: epithelial-mesenchymal transition; hepatocellular carcinoma; interaction; multifactor dimensionality reduction; polymorphisms.