Case Control Study
Copyright ©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Hepatol. Jan 27, 2021; 13(1): 109-119
Published online Jan 27, 2021. doi: 10.4254/wjh.v13.i1.109
Association of interferon lambda-4 rs12979860 polymorphism with hepatocellular carcinoma in patients with chronic hepatitis C infection
Jóice Teixeira de Bitencorte, Tássia Flores Rech, Vagner Ricardo Lunge, Deivid Cruz dos Santos, Mário Reis Álvares-da-Silva, Daniel Simon
Jóice Teixeira de Bitencorte, Tássia Flores Rech, Vagner Ricardo Lunge, Daniel Simon, PPG Biologia Celular e Molecular Aplicada à Saúde, Universidade Luterana do Brasil, Canoas 92425-900, Rio Grande do Sul, Brazil
Deivid Cruz dos Santos, Mário Reis Álvares-da-Silva, Division of Gastroenterology, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, Rio Grande do Sul, Brazil
Author contributions: de Bitencorte JT, Álvares-da-Silva MR, and Simon D were involved with conception and design of the study; de Bitencorte JT, Rech TF, and dos Santos DC were involved with acquisition of the samples and data; de Bitencorte JT performed the molecular analysis; de Bitencorte JT, Rech TF, Lunge VR, and Simon D performed the statistical analysis and interpretation of data; de Bitencorte JT, Rech TF, and Simon D drafted the manuscript; All authors read and approved the final version of the manuscript.
Supported by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior-Brasil (CAPES), No. 001.
Institutional review board statement: This study was approved by the Research Ethics Committee of Hospital de Clínicas de Porto Alegre under the protocol 15-0126.
Informed consent statement: All patients and controls gave informed consent.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Data sharing statement: No additional data are available.
STROBE statement: The authors have read the STROBE Statement—checklist of items, and the manuscript was prepared and revised according to the STROBE Statement—checklist of items.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Daniel Simon, PhD, Adjunct Professor, PPG Biologia Celular e Molecular Aplicada à Saúde, Universidade Luterana do Brasil, Av. Farroupilha, 8001 – Prédio 22–5° andar, Canoas 92425-900, Rio Grande do Sul, Brazil. daniel.simon@ulbra.br
Received: July 31, 2020
Peer-review started: July 31, 2020
First decision: October 23, 2020
Revised: November 9, 2020
Accepted: November 17, 2020
Article in press: November 17, 2020
Published online: January 27, 2021
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

These findings suggest that the T allele of IFNL4 rs12979860 polymorphism is associated with the development of cirrhosis and HCC in chronic HCV-infected patients.

Keywords: Hepatitis C, Hepatitis C virus, Cirrhosis, Hepatocellular carcinoma, Genetic polymorphism, Interferon-lambda

Core Tip: Hepatitis C virus (HCV) infection is a major public health problem worldwide as the infection progresses to severe chronic liver diseases in many patients. Interferon lambdas modulate the immune responses against infections, including the antiviral activity by promoting the expression of several genes related to immunological functions. The interferon lambda-4 rs12979860 (C/T) polymorphism, which is associated with spontaneous and treatment-induced clearance of HCV, plays a pivotal role in the host response to HCV-associated liver diseases. In this case-control study, the rs12979860 T allele was found to be associated with the development of cirrhosis and hepatocellular carcinoma in chronic HCV-infected patients.