Abstract
Background and Aims: Polymorphisms in the immune response genes can contribute to clearance of hepatitis C virus (HCV) infection but also mediate liver inflammation and cancer pathogenesis. This study aimed to investigate the association of polymorphisms in PD-1 (PDCD1), IFNL3 (IL28B), and TLR2 immune related genes in chronic HCV patients with different hepatic and lymphoproliferative HCV-related diseases.Methods: Selected PDCD1, IFNL3, and TLR2 genes were tested by molecular approaches in 450 HCV-positive patients with increasing severity of underlying liver diseases [including chronic infection (CHC), cirrhosis and hepatocellular carcinoma (HCC)], in 238 HCV-positive patients with lymphoproliferative diseases [such as cryoglobulinemia and non-Hodgkin lymphoma (NHL)] and in 94 blood donors (BD).Results: While the rs12979860 IFNL3 T allele was found a good marker associated with HCV-outcome together with the rs111200466 TLR2 del variant, the rs10204525 PD-1.6 A allele was found to have an insignificant role in patients with HCV-related hepatic disorders. Though in Asian patients the combination of IFNL3 and PD-1.6 markers better define the HCV-related outcomes, in our series of Caucasian patients the PD-1.6 A-allele variant was observed very rarely.Conclusion: Differences in the incidence of HCV-related HCC and clinical response between Asians and Europeans may be partially due to the distribution of PD-1.6 genotype that we found divergent between these two populations. On the other hand, we confirmed in this study that the polymorphic variants within IFNL3 and TLR2 immune response genes are significantly associated with HCV-related disease progression in our cohort of Italian patients.
Highlights
Hepatocellular carcinoma is the primary malignancy of the liver that often occurs in the setting of underlying chronic liver disease, mostly chronic hepatitis B (HBV) and/or C virus infection (HBV and hepatitis C virus (HCV), respectively), alcoholic liver disease, and non-alcoholic fatty liver disease
By exploring the relationship between innate immunity and HCV-related disorders we found that the IFNL3 C rs12979860 and TLR2 -196-174 ins polymorphisms, both associated with interferon-treatment response and spontaneous HCV-clearance as well as with lower HCV viral load, are associated with a decreased risk of HCV-related diseases and delay the occurrence of cirrhosis and hepatocellular carcinoma (HCC) (De Re et al, 2016)
The analysis of programmed cell death protein 1 (PD-1).6 genotype distributions among HCV-related cases, compared to that of blood donors (BD) showed no significant association with the risk of development of liver diseases or lymphoproliferative disorders
Summary
Hepatocellular carcinoma is the primary malignancy of the liver that often occurs in the setting of underlying chronic liver disease, mostly HBV and/or C virus infection (HBV and HCV, respectively), alcoholic liver disease, and non-alcoholic fatty liver disease. Curative treatment options for HCC are local resection, radioembolization and multikinase inhibitors. Available options in patients with unresectable HCC are liver transplantation, percutaneous ethanol injection, radiofrequency ablation, and transcatheter arterial chemoembolization (Hernaez and El-Serag, 2018). Most patients have locally advanced or metastatic HCC at diagnosis and are not eligible for either liver resection or transplantation. In these cases, despite the attempt to improve the OS of patients by chemotherapy, radioembolization, and multikinase inhibitor sorafenib, the OS remains poor (Llovet et al, 2008). Polymorphisms in the immune response genes can contribute to clearance of hepatitis C virus (HCV) infection and mediate liver inflammation and cancer pathogenesis. This study aimed to investigate the association of polymorphisms in PD-1 (PDCD1), IFNL3 (IL28B), and TLR2 immune related genes in chronic HCV patients with different hepatic and lymphoproliferative HCV-related diseases
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