IJCM  Vol.9 No.2 , February 2018
IL28B SNPs rs12979860 and rs8099917 Are Associated with Inflammatory Response in Argentine Chronic HCV Patients
Abstract: Background: Hepatitis C virus (HCV) is a major cause of chronic liver disease, including cirrhosis and liver cancer. The aim of our study was to determine whether IL28B single nucleotide polymorphisms (SNPs) rs12979860 and rs8099917 can be considered a prognostic host factor in untreated chronic HCV patients. Methods: We set up a real-time Allele Specific PCR amplification to determine the allele present in each polymorphic site, and statistically grouped and compared this result with clinical data. Results: We determined rs12979860 and rs8099917 genotype and allele frequencies in a single cohort of untreated chronically HCV-infected patients. We found significant associations between higher inflammatory activity, measured as ALT levels or METAVIR scores and rs12979860 CC (P = 0.0013 and P = 0.0033, respectively) and rs8099917 TT (P = 0.0005 and P = 0.0264, respectively) genotypes. Interestingly, considering both genotypes together, we also found association with ALT levels (P = 0.0003; OR = 5.125) or METAVIR scores (P = 0.0038; OR = 5.179), suggesting and additive effect on liver inflammation in these patients. Conclusion: we show association between hepatic inflammatory activity in a single Argentinean untreated chronically HCV cohort and SNPs located in the interferon lambda gene region. The studied polymorphisms, together with further innate and adaptive immune responses, clearly play a role in modulating the HCV infected patients outcome, contributing to hepatic inflammation and possible fibrosis/cirrhosis.
Cite this paper: Machicote, A. , Flichmann, D. , Arana, E. , Paz, S. , Fainboim, H. , Fainboim, L. and Fernández, P. (2018) IL28B SNPs rs12979860 and rs8099917 Are Associated with Inflammatory Response in Argentine Chronic HCV Patients. International Journal of Clinical Medicine, 9, 79-91. doi: 10.4236/ijcm.2018.92009.

[1]   WHO (2017) Global Hepatitis Report, 2017. World Health Organization, Geneva.

[2]   Kim, C.W. and Chang, K.M. (2013) Hepatitis C Virus: Virology and Life Cycle. Clinical and Molecular Hepatology, 19, 17-25.

[3]   Ge, D., Fellay, J., Thompson, A.J., Simon, J.S., Shianna, K.V., Urban, T.J., Heinzen, E.L., et al. (2009) Genetic Variation in IL28B Predicts Hepatitis C Treatment-Induced Viral Clearance. Nature, 461, 399-401.

[4]   Tanaka, Y., Nishida, N., Sugiyama, M., Kurosaki, M., Matsuura, K., Sakamoto, N., Nakagawa, M., et al. (2009) Genome-Wide Association of IL28B with Response to Pegylated Interferon-Alpha and Ribavirin Therapy for Chronic Hepatitis C. Nature Genetics, 41, 1105-1109.

[5]   Rauch, A., Kutalik, Z., Descombes, P., Cai, T., Di Iulio, J., Mueller, T., Bochud, M., et al. (2010) Genetic Variation in IL28B Is Associated with Chronic Hepatitis C and Treatment Failure: A Genome-Wide Association Study. Gastroenterology, 138, 1338-1345.

[6]   Suppiah, V., Moldovan, M., Ahlenstiel, G., Berg, T., Weltman, M., Abate, M.L., Bassendine, M., et al. (2009) IL28B Is Associated with Response to Chronic Hepatitis C Interferon-Alpha And Ribavirin Therapy. Nature Genetics, 41, 1100-1104.

[7]   Ridruejo, E., Solano, A., Marciano, S., Galdame, O., Adrover, R., Cocozzella, D., Delettieres, D., et al. (2011) Genetic Variation in Interleukin-28B Predicts SVR in Hepatitis C Genotype 1 Argentine Patients Treated with PEG IFN and Ribavirin. Ann Hepatol, 10, 452-457.

[8]   Thomas, D.L., Thio, C.L., Martin, M.P., Qi, Y., Ge, D., O’Huigin, C., Kidd, J., et al. (2009) Genetic Variation in IL28B and Spontaneous Clearance of Hepatitis C Virus. Nature, 461, 798-801.

[9]   Tillmann, H.L., Thompson, A.J., Patel, K., Wiese, M., Tenckhoff, H., Nischalke, H.D., Lokhnygina, Y., et al. (2010) A Polymorphism near IL28B Is Associated with Spontaneous Clearance of Acute Hepatitis C Virus and Jaundice. Gastroenterology, 139, 1586-1592.

[10]   Montes-Cano, M.A., García-Lozano, J.R., Abad-Molina, C., Romero-Gómez, M., Barroso, N., Aguilar-Reina, J., Núñez-Roldán, A., et al. (2010) Interleukin-28B Genetic Variants and Hepatitis Virus Infection by Different Viral Genotypes. Hepatology, 52, 33-37.

[11]   Sato, M., Kondo, M., Tateishi, R., Fujiwara, N., Kato, N., Yoshida, H., Taguri, M., et al. (2014) Impact of IL28B Genetic Variation on HCV-Induced Liver Fibrosis, Inflammation, and Steatosis: A Meta-Analysis. PLoS ONE, 9, e91822.

[12]   Balagopal, A., Thomas, D.L. and Thio, C.L. (2010) IL28B and the Control of Hepatitis C Virus Infection. Gastroenterology, 139, 1865-1876.

[13]   Kotenko, S.V., Gallagher, G., Baurin, V.V., Lewis-Antes, A., Shen, M., Shah, N.K., Langer, J.A., et al. (2003) IFN-Lambdas Mediate Antiviral Protection through a Distinct Class II Cytokine Receptor Complex. Nature Immunology, 4, 69-77.

[14]   Sheppard, P., Kindsvogel, W., Xu, W., Henderson, K., Schlutsmeyer, S., Whitmore, T.E., Kuestner, R., et al. (2003) IL-28, IL-29 and Their Class II Cytokine Receptor IL-28R. Nature Immunology, 4, 63-68.

[15]   Robek, M.D., Boyd, B.S. and Chisari, F.V. (2005) Lambda Interferon Inhibits Hepatitis B and C Virus Replication. Journal of Virology, 79, 3851-3854.

[16]   Abe, H., Ochi, H., Maekawa, T., Hayes, C.N., Tsuge, M., Miki, D., Mitsui, F., et al. (2010) Common Variation of IL28 Affects Gamma-GTP Levels and Inflammation of the Liver in Chronically Infected Hepatitis C Virus Patients. Journal of Hepatology, 53, 439-443.

[17]   Bochud, P.Y., Bibert, S., Kutalik, Z., Patin, E., Guergnon, J., Nalpas, B., Goossens, N., et al. (2012) IL28B Alleles Associated with Poor Hepatitis C Virus (HCV) Clearance Protect against Inflammation and Fibrosis in Patients Infected with Non-1 HCV Genotypes. Hepatology, 55, 384-394.

[18]   Noureddin, M., Wright, E.C., Alter, H., Clark, S., Thomas, E., Chen, R., Zhao, X., et al. (2013) Association of IL28B Genotype with Fibrosis Progression and Clinical Outcomes in Patients with Chronic Hepatitis C: A Longitudinal Analysis. Hepatology, 58, 1548-1557.

[19]   Fabris, C., Falleti, E., Cussigh, A., Bitetto, D., Fontanini, E., Bignulin, S., Cmet, S., et al. (2011) IL-28B rs12979860 C/T Allele Distribution in Patients with Liver Cirrhosis: Role in the Course of Chronic Viral Hepatitis and the Development of HCC. Journal of Hepatology, 54, 716-722.

[20]   Di Marco, V., Bronte, F., Calvaruso, V., Capra, M., Borsellino, Z., Maggio, A., Renda, M.C., et al. (2012) IL28B Polymorphisms Influence Stage of Fibrosis and Spontaneous or Interferon-Induced Viral Clearance in Thalassemia Patients with Hepatitis C Virus Infection. Haematologica, 97, 679-686.

[21]   Falleti, E., Bitetto, D., Fabris, C., Cussigh, A., Fornasiere, E., Cmet, S., Fumolo, E., et al. (2011) Role of Interleukin 28B rs12979860 C/T Polymorphism on the Histological Outcome of Chronic Hepatitis C: Relationship with Gender and Viral Genotype. Journal of Clinical Immunology, 31, 891-899.

[22]   Marabita, F., Aghemo, A., De Nicola, S., Rumi, M.G., Cheroni, C., Scavelli, R., Crimi, M., et al. (2011) Genetic Variation in the Interleukin-28B Gene Is Not Associated with Fibrosis Progression in Patients with Chronic Hepatitis C and Known Date of Infection. Hepatology, 54, 1127-1134.

[23]   Bedossa, P. and Poynard, T. (1996) An Algorithm for the Grading of Activity in Chronic Hepatitis C. Hepatology, 24, 289-293.

[24]   Fischer, J., Böhm, S., Scholz, M., Müller, T., Witt, H., George, J., Sarrazin, C., et al. (2012) Combined Effects of Different Interleukin-28B Gene Variants on the Outcome of Dual Combination Therapy in Chronic Hepatitis C Virus Type 1 Infection. Hepatology, 55, 1700-1710.

[25]   Park, S.H. and Rehermann, B. (2014) Immune Responses to HCV and Other Hepatitis Viruses. Immunity, 40, 13-24.

[26]   Ank, N., Iversen, M.B., Bartholdy, C., Staeheli, P., Hartmann, R., Jensen, U.B., Dagnaes-Hansen, F., et al. (2008) An Important Role for Type III Interferon (IFN-Lambda/IL-28) in TLR-Induced Antiviral Activity. The Journal of Immunology, 180, 2474-2485.

[27]   Shindo, H., Maekawa, S., Komase, K., Miura, M., Kadokura, M., Sueki, R., Komatsu, N., et al. (2013) IL-28B (IFN-λ3) and IFN-α Synergistically Inhibit HCV Replication. Journal of Viral Hepatitis, 20, 281-289.

[28]   Lalle, E., Bordi, L., Caglioti, C., Garbuglia, A.R., Castilletti, C., Taibi, C., Cristofari, F., et al. (2014) IFN-Alpha Receptor-1 Upregulation in PBMC from HCV Naïve Patients Carrying cc Genotype. Possible Role of IFN-Lambda. PLoS ONE, 9, e93434.

[29]   Eslam, M., McLeod, D., Kelaeng, K.S., Mangia, A., Berg, T., Thabet, K., Irving, W.L., et al. (2017) IFN-λ3, Not IFN-λ4, Likely Mediated IFNL3-IFNL4 Haplotype-Dependent Hepatic Inflammation and Fibrosis. Nature Genetics, 49, 795-800.