Role of Interferon Gamma and Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand Receptor 1 Single Nucleotide Polymorphism in Natural Clearance and Treatment Response of HCV Infection

Abstract

Hepatitis C virus (HCV) pathogenesis and treatment outcomes are multifactorial phenomena involving both viral and host factors. This study was designed to determine the role of tumor necrosis factor-related apoptosis-inducing ligand receptor 1(TRAIL-R1) and interferon gamma (IFN-γ) genetic mutations in susceptibility and response to interferon-based therapy of hepatitis C virus (HCV) infection. The detection of TRAIL-R1 rs4242392 and IFN-γ rs2069707 single nucleotide polymorphisms was completed in 118 chronic HCV patients and 96 healthy controls by allele-specific polymerase chain reaction and restriction fragment length polymorphisms polymerase chain reaction. Patients were further categorized into sustained virological responder (SVR) and nonresponder (NR) groups on the basis of their response to interferon-based therapy for HCV infection. Real-time PCR was used for HCV quantification. HCV genotyping was performed by Ohno's method. The results demonstrated that the distribution of the TRAIL-R1 rs4242392TT genotype was significantly higher in the SVR group (78%) compared to the NR group (36%). It showed that chronic HCV patients possessing the TRAIL-R1 rs4242392TT genotype are better responders to interferon-based therapy (p<0.05). The prevalence of the TRAIL-R1 rs4242392TT genotype in healthy controls and chronic HCV patients was 56% and 65% respectively. It indicated that there is the TRAIL-R1 rs4242392 genetic variation plays no role in the spontaneous clearance of HCV infection (p>0.05). The distribution of IFN-γ rs2069707 was the opposite to TRAIL-R1 rs4242392 prevalence, that is, there was high distribution of the IFN-γ rs2069707GG genotype in patients and healthy controls (p<0.05), while the prevalence of IFN-γ rs2069707GG in SVR and NR groups was comparable (p>0.05). In conclusion, genetic variation of TRAIL-R1 rs4242392 is linked with response to interferon-based therapy for HCV infection, and genetic variation IFN-γ rs2069707 is associated with natural clearance of HCV infection.

Association of interferon gamma gene polymorphism and susceptibility to hepatitis C virus infection in Egyptian patients: A multicenter, family‐based study

“…Comparing the distribution of (−764 G/C, rs2069707) alleles between the three groups revealed that the carriage of C allele was significantly higher in SVC than the CHC and control groups, and this was in agreement with the study by Azam et al ., who found that there was a strong association between the IFN‐γ genotype rs2069707GG and the spontaneous clearance of HCV …”

“…Comparing the distribution of (−764 G/C, rs2069707) alleles between the three groups revealed that the carriage of C allele was significantly higher in SVC than the CHC and control groups, and this was in agreement with the study by Azam et al, who found that there was a strong association between the IFN-γ genotype rs2069707GG and the spontaneous clearance of HCV. 14 Others stated that the −764 G allele was associated with a higher level of IFN-γ than the −764 C allele, and no mutation was detected in the −764 position. 35 Another study reported that the association of the −764 G alleles with spontaneous recovery was not as strong as the association with treatment response.…”

“…The SNP (rs2069707 C/G) of the IFN‐γ gene is located in the proximal promoter region at position −764, next to the binding motif for HSF1 . Some data support the hypothesis that the SNP variant −764 G is an important genetic marker for treatment response and spontaneous recovery in HCV infection …”

“…10 Some data support the hypothesis that the doi:10.1002/jgh3.12024 SNP variant −764 G is an important genetic marker for treatment response and spontaneous recovery in HCV infection. 13,14 Other studies demonstrated that IFN-γ SNPs appear to affect IFN-γ expression, such as rs2069709, which is a G to T transition at position −179 bp in the promoter region. 11 Several studies on (−179 G/T, rs2069709) showed that SNP has been implicated in several autoimmune and chronic inflammatory conditions.…”

TNF-Related Apoptosis-Inducing Ligand: Non-Apoptotic Signalling

“…TRAIL is expressed as cell surface protein, mostly by activated immune cells such as T and B cells [ 181 ], neutrophils [ 182 , 183 , 184 ], dendritic cells [ 185 ], monocytes and macrophages [ 186 , 187 , 188 , 189 , 190 ], natural killer and NKT cells (NK) [ 191 , 192 , 193 , 194 , 195 , 196 , 197 , 198 , 199 , 200 , 201 ]. TRAIL play a crucial role both during viral clearance [ 202 , 203 , 204 , 205 , 206 , 207 , 208 , 209 , 210 , 211 , 212 , 213 , 214 ] and tumour immune surveillance [ 215 , 216 , 217 , 218 , 219 , 220 ]. Mechanistically, during innate immunity, NK cells and CTLs (cytotoxic T cells) promote apoptosis of target cells, either by releasing soluble factors such as the cytolytic granules [ 184 , 221 , 222 , 223 ], which contain perforin and granzymes, or by engaging membrane-bound death ligands like FasL or TRAIL [ 200 , 221 , 224 , 225 , 226 , 227 ,…”