PDCD1 and IFNL4 genetic variants and risk of developing hepatitis C virus‐related diseases

Abstract

Background: Genetic variants of IFNL4 and PDCD1 genes have been shown to influence the spontaneous clearance of hepatitis C virus (HCV) infection. We investigated the IFNL4 rs12979860 and the PDCD1 polymorphisms in 734 HCV-positive patients, including 461 cases with liver disease of varying severity and 273 patients with lymphoproliferative disorders to determine the association of these genes with patient's outcome. Methods: Expression levels of PDCD1 mRNA encoded by haplotypes were investigated by quantitative PCR in hepatocellular carcinoma (HCC) tissue and peripheral blood mononuclear cells. Flow cytometry was used to detect PD-1 and its ligand PD-L1. Results: The frequency of IFNL4 rs12979860 C/T or T/T genotypes was significantly higher in patients with HCV-related diseases than blood donors (P < .0001). Patients expressing the IFNλ4 variant with one amino acid change that reduces IFNλ4 secretion was found increased in frequency in HCV-related diseases compared to HCC PDCD1 mRNA levels in HCC tissue were significantly higher in cases carrying the PD-1.3 A or the PD-1.7 G allele (P = .0025 and P = .0167). Linkage disequilibrium (LD) between PD-1.3 and IFNL4 was found in patients with mixed cryoglobulinaemia (MC) only (LD = 0 in HCC; LD = 72 in MC). PBMCs of MC patients expressed low levels of PD-L1 in CD19+IgM+B cells and of PD-1 in CD4+T cells suggesting the involvement of regulatory B cell-T cell interaction to the pathogenesis of MC. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Clinical Significance of Telomerase Reverse-Transcriptase Promoter Mutations in Hepatocellular Carcinoma

“…Comprehensive genomic studies recognised the high molecular heterogeneity of HCC resulting from the complex interplay between viral and non-viral risk factors along with host susceptibility, such as the genetic polymorphisms in the immune response genes [14][15][16]. Mutations in oncosuppressors and oncogenes have shown to be relatively frequent in HCC and to affect more than 10 signalling pathways defined as major players of hepatocarcinogenesis [17].…”

Variants of IFNL4 Gene in Amazonian and Northern Brazilian Populations

“…This variability is often caused by a single allele, which can condition a better or worse resolution of viral infections and therapeutic responses [22][23][24]. As an example, we have the rs12979860-C/T variant in which the allelic replacement of T by C conditioned sustained virological response (SVR) in European and Asian populations, in addition to a better response to treatments with sofosbuvir [25][26][27].…”

Some concerns about “PDCD1 and IFNL4 genetic variants and risk of developing hepatitis C virus‐related diseases”

“…With great interests, I carefully read the article by Valli De Re et al in a recent issue of Liver International 1 . The authors conducted a cohort study assessing the associations of polymorphisms of IFNL4 and PDCD1 genes on 734 hepatitis C virus (HCV)‐positive patients, including 461 cases with liver disease of varying severity and 273 patients with lymphoproliferative disorders.…”