Abstract
IFNL3/IFNL4 polymorphisms are inversely associated with the risk of chronic hepatitis C virus (HCV) infection and cirrhosis, two major risk factors for developing hepatocellular carcinoma (HCC). To further explore these inverse associations and their molecular underpinnings, we analyzed IFNL3/IFNL4 polymorphisms represented by the IFNL4 genotype (presence of rs368234815-dG or rs12979860-T alleles) in HCV patients: 2969 from Japan and 2931 from Taiwan. IFNL4 genotype was associated with an increased risk of HCV-related HCC (OR=1.28, 95%CI=1.07-1.52, P=0.0058) in the general population of Japanese patients, but not in Taiwanese patients who achieved treatment-induced viral clearance. IFNL4 genotype was also associated with a decreased risk of cirrhosis (OR=0.66, 95%CI=0.46-0.93, P=0.018, in Taiwanese patients). We then engineered HepG2 cells to inducibly express IFN-λ4 in the presence or absence of interferon lambda receptor 1 (IFNLR1). Induction of IFN-λ4 resulted in its intracellular accumulation, mainly in lysosomes and late endosomes, and increased ER stress, leading to apoptosis and reduced proliferation. We identified the very-low-density lipoprotein receptor (VLDLR), which facilitates HCV entry into hepatocytes, as a transcript induced by IFN-λ4 but not IFN-λ3. Our results suggest that the molecular mechanisms underlying the anti-cirrhotic but pro-HCV associations observed for IFNL3/IFNL4 polymorphisms are, at least in part, contributed by intracellular accumulation of IFN-λ4 causing ER stress in hepatic cells.
Highlights
Infection with hepatitis C virus (HCV) persists in a chronic stage in 75-85% of infected individuals; 10-20% of these patients progress to liver cirrhosis and to hepatocellular carcinoma (HCC), the main type of primary liver cancer, with a rate of 1-4% per year [1]
When we overexpressed interferon lambda 4 (IFN-l4) in LX2, to hepatocytes, we observed upregulation of endoplasmic reticulum (ER) stress genes and inhibition of cell proliferation (Figures 3D–G). These results suggest that decreased proliferation of activated hepatic stellate cells (HSCs), which has been shown to contribute to reduced cirrhosis [47], could partly explain the association of IFNL4 genotype with reduced cirrhosis in patients with HCV
We observed a moderately increased risk of progression to HCC in HCV patients with IFNL4 genotype in the general population, but this risk was eliminated in patients achieving viral clearance, explaining inconsistencies in previous reports on HCC risk [10,11,12,13,14,15]
Summary
Infection with hepatitis C virus (HCV) persists in a chronic stage in 75-85% of infected individuals; 10-20% of these patients progress to liver cirrhosis and to hepatocellular carcinoma (HCC), the main type of primary liver cancer, with a rate of 1-4% per year [1]. Genetic polymorphisms within the IFNL3/IFNL4 genomic region have been identified as the strongest predictors of spontaneous and treatment-induced clearance of HCV infection [2,3,4,5]. Due to strong linkage disequilibrium (LD) in the IFNL3/IFNL4 region [6], many markers provide similar genetic associations, including rs368234815 that controls IFN-l4 production [7], rs4803217 that was suggested to affect IFN-l3 stability [8], and rs12979860, a non-functional polymorphism in the first intron of IFNL4 [3]. Individuals with the rs368234815-dG allele have a frameshift in the first exon of the IFNL4 gene, which creates an open reading frame for interferon lambda 4 (IFN-l4), a type III IFN. Homozygous carriers of the rs368234815-TT allele, including most Asians (~90%) and Europeans (~50%), but only a minority of individuals of African ancestry (~10%), are natural IFN-l4 knockouts [6]
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