Hepatitis C is a chronic liver disease of major public health concern, caused by Hepatitis C virus (HCV) (Tariq et al., 2016). The infection causes various complications especially liver cirrhosis (LC) and hepatocellular carcinoma (HCC) that may lead to death (Neamatallah et al., 2020). About 50 million people suffer from chronic HCV infection globally and the annual mortality rate is about 2.5 million deaths (Bashir et al., 2017). HCV is a single stranded RNA virus of approximately 9.6 kb length (Nasir et al., 2024, Seeger et al., 2020). The HCV infected cells release secretary antiviral cytokines called interferon’s (IFNs), particularly IFN-γ (Pravica et al., 2000). The variations in the IFN-γ gene affect the expression that may leads to alter disease dynamics (Khanizadeh et al., 2011).

The IFN-γ gene consists of four exons and three introns located on chromosome 12 (q24) (Alspach et al., 2019). The IFN-γ protein encoded is composed of 146 amino acids mainly produced by effector T cells, CD4 + , CD8 + , Th1 cells, and natural killer cells (Nasir et al., 2024, Bouzgarrou et al., 2009). IFN-γ increases T-cell cytotoxicity and natural killer cell activity as well as enhances cellular immune responses (Bouzgarrou et al., 2009). It is vital for host defense and counteracts the viral replication either by direct inhibition i.e. inhibition of HCV receptors such as Cludin-1, CD81 or via activation of the immunoregulatory mechanisms responsible for the control of infection (Urban et al., 2012). IFN-γ also suppresses the activity of HCV by affecting the viral RNA and protein coat (Sheneef et al., 2017). It also increases immune lysis of virus infected cells, prevents hepatic fibrosis and reduces the risk of HCV induced carcinogenesis (Sun et al., 2015). IFN-γ protein binds to IFN-γ receptor-1 expressed on all monocytes, macrophages, T cells, B cells, NK cells, neutrophils, etc (Chaim, 2012). The gene for IFN-γR1 is located on chromosome 6(q23), composed of seven exons and six introns (He et al., 2017). It encodes IFN-γR1 chain of 489 amino acids (Van de Vosse and Van Dissel, 2017). The genetic variation in IFN-γR1 gene may affect the binding of IFN-γ protein that lead to adverse disease outcomes (Khanizadeh et al., 2012a).

The genetic variation in different regions of IFN-γ and IFN-γR1 genes are reported and associated with various diseases (Sun et al., 2015, Khanizadeh et al., 2012a). The genetic variation in IFN-γR1 gene may reduce receptor function that might lead to the severity of infection by decreasing the IFN-γ attachment with receptors (Nalpas et al., 2010). The polymorphisms in various parts of IFN-γ gene may affect the gene expression (Alvarez et al., 2023) as in interon-1 associated with pulmonary tuberculosis, hepatitis B, cancer, malaria, multiple sclerosis and schistosomiasis (Bouzgarrou et al., 2009, Ayensu, 2018). The variation in the promoter of IFN-γR1 gene is associated with pathogenesis of Hepatitis B virus (HBV) infection and severe hepatic fibrosis (Zhou et al., 2009).

HCV is a serious health issue around the globe and the infection rate is continuously increasing. The mortality and morbidity due to LC and HCC are also alarming and the different genotypes of HCV are significant contributors to this situation (Malik and Khalil, 2024). The reported prevalence of HCV infection from Pakistan is 11.55 % and LC prevalence ranges from 20 % to 25 % (Bouzgarrou et al., 2009). Globally the most prevalent HCV genotypes are 1, 2 and 3 whereas in Pakistan 1 and 3 genotypes are predominantly found (Haqqi et al., 2019). The annual mortality rate due to HCV infection in Pakistan is 1.6 % (Farhan et al., 2023). The IFN-γ and its receptor (IFN-γR1) play key role in the prevention of HCV infection and polymorphisms in these genes may cause various infection outcomes (Bahgat et al., 2015). The intron part of IFN-γ gene and promoter region of IFN-γR1 gene are important in this context. Some studies from different parts of the world showed the IFN-γ and IFN-γR1 genes association with various infection and HCV (Habeeb et al., 2021). Data regarding the genes under study in connection to HCV are not available from Pakistan. Therefore, the current study is designed to analyze genetic variability in IFN-γ genes and study association of HCV disease outcome in HCV positive patients from Peshawar Pakistan.