HCV-related liver and lymphoproliferative diseases: association with polymorphisms of IL28B and TLR2

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// Valli De Re 1,* , Mariangela De Zorzi 1,* , Laura Caggiari 1 , Gianfranco Lauletta 2 , Maria Lina Tornesello 3 , Elisa Fognani 4 , Marta Miorin 5 , Vito Racanelli 6 , Luca Quartuccio 7 , Laura Gragnani 4 , Sabino Russi 2 , Fabio Pavone 2 , Michela Ghersetti 8 , Elena Garlatti Costa 8 , Pietro Casarin 8 , Riccardo Bomben 9 , Cesare Mazzaro 9 , Giancarlo Basaglia 10 , Massimiliano Berretta 11 , Emanuela Vaccher 11 , Francesco Izzo 12 , Franco Maria Buonaguro 3 , Salvatore De Vita 7 , Anna Linda Zignego 4 , Paolo De Paoli 13 and Riccardo Dolcetti 14,15 1 Bio-Proteomics Facility/ Cancer Bioimmunotherapy, Department of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy 2 Liver Unit, Division of Internal Medicine and Clinical Oncology, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy 3 Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori “Fondazione G. Pascale” - IRCCS, Napoli, Italy 4 Interdepartmental Center for Systemic Manifestations of Hepatitis Virus MASVE, Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy 5 Cytogenetics and Molecular Biology Unit, Santa Maria degli Angeli Hospital Pordenone, Pordenone, Italy 6 Immunology Section, Department of Biomedical Sciences and Human Oncology, University of Bari Medical School, Bari, Italy 7 Clinic of Rheumatology, Department of Medical and Biological Sciences, University Hospital “Santa Maria della Misericordia”, Udine, Italy 8 Internal Medicine-Liver Unit, Santa Maria degli Angeli Hospital Pordenone, Pordenone, Italy 9 Clinical and Experimental Onco-Hematology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy 10 Microbiology-Immunology and Virology Unit, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy 11 Medical Oncology, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy 12 Hepatobiliary Unit, Istituto Nazionale Tumori “Fondazione G. Pascale” - IRCCS, Napoli, Italy 13 Scientific Directorate, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy 14 Cancer Bio-Immunotherapy, Department of Translational Research, Centro di Riferimento Oncologico (CRO), National Cancer Institute, Aviano, Italy 15 University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Queensland, Australia * These authors have equally contributed to this study as first authors Correspondence to: Valli De Re, email: // Keywords : HCV, TLR2, IL28B, HCC, NHL, Immunology and Microbiology Section, Immune response, Immunity Received : February 12, 2016 Accepted : April 19, 2016 Published : May 11, 2016 Abstract To explore the relationship between innate immunity and hepatitis C Virus (HCV) in determining the risk of cirrhosis (CIR), hepatocellular carcinoma (HCC), mixed cryoglobulinemia syndrome (MCS) and non-Hodgkin lymphoma (NHL), we investigated the impact of the toll-like receptor-2 (TLR2) and interleukin-28B (IL28B) genetic variants. TLR2 -174 del variant was associated with TLR2 expression and with specific downstream molecules that drive the expression of different interleukins; rs12979860 Il28B was important in response to interferon-treatment and in spontaneous clearance of HCV. The risk for liver and lymphoproliferative diseases in HCV progression was clarified by stratifying 862 HCV-positive patients into groups based on liver (CIR, HCC) and lymphoproliferative HCV-related diseases (MCS, NHL) and compared with chronic HCV (CHC) infection. Analysis of TLR2-IL28B haplotypes showed an association of wild type haplotype with the lymphoproliferative diseases (OR 1.77, p = 0.029) and a slight increase in HCV viral load (HR 1.38, p = 0.054). Wild type haplotype (TLR2 ins/ins- IL28B C/C) was also found associated with older age in patients with an hepatic diseases (in CIR and in HCC p = 0.038 and p = 0.020, respectively) supporting an effect of innate immunity in the liver disease progression. TLR2 and IL28B polymorphisms in combination showed a role in the control of HCV viral load and different HCV disease progression.

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