Association of interferon lambda-4 rs12979860 polymorphism with hepatocellular carcinoma in patients with chronic hepatitis C infection

Abstract

BACKGROUND Hepatitis C virus (HCV) infection is a public health concern worldwide. Several factors, including genetic polymorphisms, may be evolved in the progression of HCV infection to liver diseases. Interferon lambdas (IFNLs) modulate the immune response during viral infections. IFNLs induce antiviral activity, interfering in the viral replication by promoting the expression of several genes that regulate immunological functions. The interferon lambda-4 ( IFNL4 ) rs12979860 polymorphism, which is characterized by a C to T transition in intron 1, is associated with spontaneous and treatment-induced clearance of HCV infection and may play a role in the development of HCV-associated liver diseases, including hepatocellular carcinoma (HCC). AIM To investigate the association of IFNL4 rs12979860 polymorphism with fibrosis, cirrhosis, and HCC in patients with chronic HCV infection. METHODS This study was comprised of 305 chronic HCV-infected patients (53 fibrosis, 154 cirrhosis, and 98 HCC cases). The control group was comprised of 260 HCV-negative healthy individuals. The IFNL4 rs12979860 polymorphism was genotyped using the TaqMan assay. Fibrosis was diagnosed based on liver biopsy findings, while cirrhosis was diagnosed through clinical, laboratory, anatomopathological, and/or imaging data. HCC was diagnosed through imaging tests, tumor, and/or anatomopathological markers. RESULTS The T allele was observed in the three groups of patients (fibrosis, cirrhosis, and HCC) at a significantly higher frequency when compared with the control group ( P = 0.047, P < 0.001, and P = 0.01, respectively). Also, genotype frequencies presented significant differences between the control group and cirrhosis patients ( P < 0.001) as well as HCC patients ( P = 0.002). The risk analysis was performed using the codominant and dominant T allele models. In the codominant model, it was observed that the CT genotype showed an increased risk of developing cirrhosis in comparison with the CC genotype [odds ratio (OR) = 2.53; 95% confidence interval (CI): 1.55-4.15; P < 0.001] as well as with HCC (OR = 2.54; 95%CI: 1.44-4.56; P = 0.001). A similar result was observed in the comparison of the TT vs CC genotype between the control group and cirrhosis group (OR = 2.88; 95%CI: 1.44-5.77; P = 0.001) but not for HCC patients. In the dominant T allele model, the CT + TT genotypes were associated with an increased risk for progression to cirrhosis (OR = 2.60; 95%CI: 1.63-4.19; P < 0.001) and HCC (OR = 2.45; 95%CI: 1.42-4.31; P = 0.001). CONCLUSION ...

The Impact of interferon lambda 3 Polymorphism on Hepato-Cellular Carcinoma Progression in Hepatitis C Virus Patients: Treatment-Naïve and Experienced

“…HCC accounts for 80% of all primary liver cancers, and it is ranked as the fifth most common cancer and the third leading cause of cancer death in the world (de Bitencorte et al, 2021). HCC development is very complex with the contribution of several etiological and risk factors, including viral factors (e.g., HCV and hepatitis B virus (HBV)) and nonviral factors (e.g., alcohol and diabetes) (Makarova-Rusher et al, 2016).…”

“…Interferon lambda 3 (IFN-λ3) is a proinflammatory cytokine that plays a crucial role in combating HCV by regulating the transcription of interferon-stimulating genes. The IFN-λ3-encoding gene is located on chromosome 19q13 (de Bitencorte et al, 2021). Several studies, including ours, have found that the rs12979860 single nucleotide polymorphism (SNP) present upstream of IFN-λ3 (~3 kb) has high predictive power for clinical (e.g., the progression of hepatic fibrosis) and treatment (e.g., the response to pegylated-IFNα plus ribavirin therapy and DAA therapy) outcomes in the case of HCV infection (El-Awady et al, 2012;Ge et al, 2009;Marwa 2021;Rauch et al, 2010;Tanaka et al, 2009;Thomas et al, 2009).…”