The Synergistic Effect of TNF-308G/A and TGF1-509C/T Polymorphisms on Hepatic Fibrosis Progression in Hepatitis C Virus Genotype 4 Patients

Tumor necrosis factor-alpha (TNF) and transforming growth factor-beta (TGF1) cytokines are highly implicated in liver fibrosis. Polymorphisms in these cytokines affect their expression, secretion, and activity. This study aimed to evaluate the influence of TNF-308G/A and TGF1-509C/T polymorphism on hepatic fibrosis progression in Egyptian patients with hepatitis C virus (HCV) genotype 4. Genotyping of TNF-308G/A and TGF1-509 C/T was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 122 subjects (50 healthy controls and 72 HCV patients). Also, serum TNF and TGF1 levels were detected by enzyme-linked immunosorbent assay (ELISA). The genotyping results of early (F0-F1, n=36) and late (F2-F4, n=36) HCV fibrosis patients showed that late fibrosis patients had higher TNF-308 AA genotype and TGF1-509 TT genotype than early fibrosis patients (p=0.016, 0.028, respectively). Moreover, the TNF and TGF1 serum levels were significantly higher in HCV patients with TNF A containing genotypes (GA+AA) (p=0.004) and patients with TGF1T containing genotypes (CT+TT) (p=0.001), respectively. The combined unfavorable TNF (GA/AA) and TGF1 (CT/TT) genotypes were highly associated with abnormal liver function parameters and were significantly higher in high activity (A2-A3) and late fibrosis (F2-F4) HCV patients (p=0.023, 0.029). The multivariate analysis results confirmed that the combined TNF-308 (AA) and TGF1-509 (TT) unfavorable genotypes increased the risk of hepatic fibrosis progression by 6.4-fold than combined favorable genotypes (odds ratio: 6.417, 95% confidence interval [1.490-27.641], p=0.013). In conclusion, both TNF-308G/A and TGF1-509C/T polymorphisms synergistically influence the hepatic fibrosis progression and can be used as potential biomarkers to predict hepatic disease progression in chronic hepatitis C patients.