Cytokines genes polymorphisms in chronic hepatitis C: Impact on susceptibility to infection and response to therapy Heba F. Pasha a,⇑ , Mohamed I. Radwan b , Hoda A. Hagrass c , Enas A. Tantawy d , Mohamed H. Emara b a Medical Biochemistry Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt b Tropical Medicine Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt c Clinical Pathology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt d Microbiology and Immunology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt article info Article history: Received 29 April 2012 Received in revised form 31 October 2012 Accepted 2 November 2012 Available online xxxx Keywords: Hepatitis C Cytokines Polymorphism Pegylated interferon abstract Background: Cytokines play a key role in the regulation of immune responses. In hepatitis C virus infec- tion, the production of abnormal cytokine levels appears to contribute in the progression of the disease, viral persistence, and affects response to therapy. Cytokine genes polymorphisms located within the cod- ing/regulatory regions have been shown to affect the overall expression and secretion of cytokines. The aim of the study was to evaluate the association of of IL28B rs12979860, TGF-b1-509, TNF-a 308, and IL-10-1082 polymorphisms with the susceptibility to hepatitis C virus genotype 4 infection and response to pegylated interferon-a and ribavirin therapy. Methods: IL28B, TGF-b1 and TNF-a genes polymorphisms were genotyped using polymerase chain reac- tion (PCR)-based restriction fragment length polymorphism assay while IL-10 gene polymorphism was detected by sequence specific primer-PCR in 220 healthy individuals and 440 hepatitis C infected patients (220 sustained virological response and 220 non-responder to combination therapy). Results: IL28 B CT and TT, TGF-b1 CT and TT and TNF-a AG and AA genotypes were significantly associ- ated with susceptibility to hepatitis C infection and response to therapy. While no association was found between IL-10 gene polymorphism and susceptibility to HCV infection and response to treatment. Conclusions: These results suggested that inheritance of IL28B CT and TT, TGF-b1 CT and TT and TNF-a AG and AA genotypes which appear to affect the cytokine production may be associated with susceptibility to HCV infection and resistance to combined antiviral therapy. Ó 2012 Elsevier Ltd. All rights reserved. 1. Introduction Hepatitis C virus (HCV) is a major cause of chronic liver disease, with more than 170 million infected individuals worldwide [1,2] and it is the most common cause of liver disease and public health problem in Egypt [3]. Hepatitis C virus projections based on the current prevalence of infection and anticipated rates of progression suggest that morbidity and mortality as well as the costs of medi- cal care for HCV infection will increase alarmingly in the next two decades [1]. Six major genotypes [4–9] and more than 50 subtypes of HCV have been described [5]. In general, HCV genotype 4 (HCV-4) is predominant in Africa and the Middle East [6]. In Egypt, where hepatitis C is highly endemic (up to 15% of the general population), 91% of the patients are infected with HCV genotype 4 [7] and that is why HCV genotyping is not routinely performed before therapy [8]. The currently recommended therapy for chronic HCV is the combination of pegylated interferon alpha (PEG-IFN) and ribavirin (RBV) that proved superior to standard interferon alpha and ribavi- rin [10–12]. For patients with HCV-4 infections (the prevalent genotype in Egypt), combination treatment with PEG-IFN and weight based RBV administered for 48 weeks seems to be appro- priate regimen [13]. Unfortunately, the rate of sustained virological response (SVR) is around 50% in genotype 1 and 4 infected patients [1,2,10–12]. Be- cause a significant number of patients will fail to respond or will have significant side effects, it is of major interest for both patient care and economic approach to predict non-responder (NR) [14,15]. Several viral and host-related factors determine the outcome of PEG-IFN/RBV treatment in patients with chronic HCV infection [15]. Cytokines play a key role in regulating antiviral immune re- sponses. The capacity of cytokine production in an individual might depend on a major genetic contribution. This is supported by observations of striking differences among individuals in terms of their ability to produce a particular cytokine. The association of a cytokine gene polymorphism has been reported in infectious 1043-4666/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.cyto.2012.11.003 ⇑ Corresponding author. Tel.: +20 105788030; fax: +20 552301523. E-mail address: hebapasha@yahoo.com (H.F. Pasha). Cytokine xxx (2012) xxx–xxx Contents lists available at SciVerse ScienceDirect Cytokine journal homepage: www.journals.elsevier.com/cytokine Please cite this article in press as: Pasha HF et al. Cytokines genes polymorphisms in chronic hepatitis C: Impact on susceptibility to infection and response to therapy. Cytokine (2012), http://dx.doi.org/10.1016/j.cyto.2012.11.003