IFN-λ4 may contribute to HCV persistence by increasing ER stress and enhancing IRF1 signaling

Abstract

ABSTRACT

Chronic hepatitis C virus (HCV) infection and cirrhosis are major risk factors for developing hepatocellular carcinoma (HCC). Genetic polymorphisms in the IFNL3/IFNL4 locus have been associated both with impaired clearance of HCV and protection from liver fibrosis, an early stage of cirrhosis. Here, we aimed to address the genetic and functional relationships between IFNL3/IFNL4 polymorphisms, HCV-related cirrhosis, and HCC risk. We evaluated associations between IFNL4 genotype, defined as the presence of rs368234815-dG or rs12979860-T alleles, with cirrhosis and HCC risk in patients with chronic HCV - 2,931 from Taiwan and 3,566 from Japan. We detected associations between IFNL4 genotype and decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwan), but increased risk of HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058, in Japan). In-vitro, IFN-λ4 expression increased ER stress, and enhanced positive regulation of IFN responses via IRF1 induction, which mediated antiproliferative effects in hepatic cells. Our data present novel IFN-λ4-associated pathways that may be contributing to HCV persistence and development of HCC.

Competing Interest Statement

Conflict of interest: T.R.O'B and L.P-O. are co-inventors on IFN-λ4-related patents issued to NCI/NIH and receive royalties for antibodies for IFN-λ4 detection. Other authors have nothing to declare

Footnotes

* Author names in bold designate shared co-first authorship

* Conflict of interest: T.R.O’B and L.P-O. are co-inventors on IFN-λ4-related patents issued to NCI/NIH and receive royalties for antibodies for IFN-λ4 detection. Other authors have nothing to declare

* ¹study concept and design;

* ²acquisition of data;

* ³analysis and interpretation of data;

* ⁴drafting of the manuscript;

* ⁵critical revision of the manuscript for important intellectual content;

* ⁶statistical analysis;

* ⁷obtained funding; technical, or material support;

* ⁸study supervision.

* Funders had no role in study design; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript, and decision to submit the manuscript for publication.

* The RNA-seq dataset for 108 samples (54 individual samples in duplicates) was submitted to NCBI Gene Expression Omnibus (GEO) with an accession number GSE145038 and is accessible through the link https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE145038

* Until the dataset becomes public, it can be anonymously viewed by entering a token “mnajagaebxmfber” into the box.

* To show the co-first authorship in bold letters