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:
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.
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
Research background

As a serious public health problem worldwide, hepatitis C virus (HCV) infection has unfavorable trends in morbidity and mortality. Due to high hepatotrophic potential, HCV may cause chronic complications, such as fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). Progression to chronic liver disease usually varies and is influenced by different factors, including genetic factors. The interferon lambda-4 (IFNL4) rs12979860 polymorphism, characterized by a C to T transition in the intron 1, has been associated with spontaneous and treatment-induced clearance of HCV infection and may play a role in HCV-associated liver diseases, including HCC.

Research motivation

Although the rs12979860 polymorphism has a relevant and well-known role in the spontaneous and treatment-induced clearance of HCV infection, the importance of genetic variants of this polymorphism in the progression of HCV-associated liver diseases is still unclear.

Research objectives

We aimed to investigate the potential role of the variants in the progression to hepatic fibrosis, cirrhosis, and HCC in chronic HCV-infected patients. In addition, the distribution of the rs12979860 IFNL4 genetic variants was analyzed in accordance with clinical features of patients.

Research methods

This case-control study included 305 patients with chronic HCV infection patients (53 with fibrosis, 154 with cirrhosis, and 98 with HCC), and 260 HCV-negative healthy individuals as controls. Diagnosis of fibrosis (METAVIR F1-F3) was performed by liver biopsy findings, while the diagnosis of cirrhosis was performed through clinical, laboratorial, anatomopathological, and/or imaging data. Lastly, diagnosis of HCC was performed through dynamic imaging tests, and/or anatomopathological markers. Patients with HCV/human immunodeficiency virus and/or HCV/ hepatitis B virus coinfection were excluded. Molecular analysis was performed using validated pre-designed real-time PCR TaqMan® Assays.

Research results

A higher frequency of the T allele was observed among the groups of patients (fibrosis, cirrhosis, and HCC) as compared to the controls: (P = 0.047; P < 0.001; and P = 0.01, respectively). Also, significant differences were observed concerning genotype frequencies between HCC (P = 0.002) and cirrhosis patients (P < 0.001) in comparison with controls. Two genetic models were tested in the risk analysis: Codominant model and dominant T allele model. In the codominant model, it was observed that the CT genotype was related to an increased risk of cirrhosis [odds ratio (OR) = 2.53; 95% confidence interval (CI): 1.55-4.15; P < 0.001] and HCC (OR = 2.54; 95%CI: 1.44-4.56; P = 0.001) as compared to CC genotype. In the comparison of the TT vs CC genotype, a significant difference was observed between the control group and cirrhosis group (OR = 2.88; 95%CI: 1.44-5.77; P = 0.001) but not the HCC group. In the dominant T allele model, the CT + TT genotypes confer an increased risk for the 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). Finally, a significant higher frequency of the T allele among patients with HCV genotypes 1 and 3 (92% and 67%, respectively; P = 0.017) and a higher frequency of TT genotype among patients with hepatic encephalopathy (P = 0.03) was observed.

Research conclusions

This study suggests that the T allele from IFNL4 rs12979860 polymorphism is associated with the development of cirrhosis and HCC in chronic HCV-infected patients.

Research perspectives

As an important factor related to spontaneous and treatment-induced clearance of HCV infection, the analysis of IFNL4 rs12979860 polymorphism in the present study may provide a better understanding of the genetic variants with disease progression and clinical features. In order to clarify this issue, large samples are needed to verify the association of genetic polymorphisms with hepatitis C as well as the correlation of genetic variants with gene expression and protein interactions.