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

By Olusegun O Onabajo, Fang Wang, Mei-Hsuan Lee, Oscar Florez-Vargas, Adeola Obajemu, Mauro A.A Castro, Chizu Tanikawa, Joselin Vargas, Shu-Fen Liao, Ci Song, Yu-Han Huang, Chen-Yang Shen, A. Rouf Banday, Thomas R O'Brien, Zhibin Hu, Koichi Matsuda, A. Gordon Robertson, Ludmila Prokunina-Olsson

Posted 29 Oct 2020
bioRxiv DOI: 10.1101/2020.10.28.359398

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

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