Two novel SNPs in the promoter region of PKR gene in hepatitis C patients and their impact on disease outcome and response to treatment |
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Authors: | Dina El-Dahshan Doaa Bahy Ahmed Wahid Amr E. Ahmed Amro Hanora |
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Affiliation: | 1. Department of Clinical Pathology, Faculty of Medicine, Beni-Suef University, Beni-Suef, Egypt;2. Biotechnology Department, Faculty of Postgraduate Studies for Advanced Sciences, Beni-Suef University, Beni-Suef, Egypt;3. Beni-Suef Health Insurance Hospital, Beni-Suef, Egypt;4. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt;5. Microbiology and Immunology Department, Faculty of Pharmacy, Suez Canal University, Ismailia, Egypt |
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Abstract: | Background and study aimsThe double-stranded RNA dependent protein kinase (PKR) plays a vital role in the immune system. During HCV infection, PKR has antiviral effect by inhibition of protein synthesis of the HCV. The functional single nucleotide polymorphisms (SNPs) in PKR promoter region might have a relation to HCV disease outcome and response to treatment. The objective of the present work was threefold. First, it proposed an optimized protocol for PCR amplification of PKR promoter. Second, it screened the promoter region of PKR gene in HCV Egyptian patients to detect the possible SNPs’ function. Third, to study the association between the detected SNPs and the response to treatment.Patients and methodsThe functional SNPs in PKR promoter region were detected using DNA sequencing in 40 HCV infected patients; 20 sustained virologic response (SVR) patients and 20 nonresponse (NR) patients after combined interferon/ribavirin therapy. Twenty healthy subjects were included as a control.ResultsTwo functional SNPs were detected: rs62133148T>G and rs12992188C>T within our target PKR promoter region. In rs62133148 polymorphism, there is a significant difference between patients and control subjects for TT and TG genotypes (p?0.0001). In addition, the G allele is more predominant in HCV patients. In rs12992188 polymorphism, the CC genotype is significantly different between patients and healthy control subjects (OR/95% CI: 0.033/0.006–0.172, p?0.0001). The presence of C allele was significantly associated with the NR patients (OR/95%CI: 0.25/0.097–0.643, p?=?0.006). The TT genotype is significantly different between SVR and NR (OR/95%CI: 8.5/1.54–46.871, p?=?0.014).ConclusionThis study is a pioneer clinical study on these two functional SNPs (rs62133148T>G and rs12992188 C>T). The rs62133148 polymorphism does not show any association with response to treatment. The TT genotype in rs12992188 polymorphism shows association with response to treatment. Therefore, patients with TT genotypes were more likely to achieve SVR. |
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Keywords: | PKR RNA-dependant protein kinase EIF2AK2 eukaryotic translation initiation factor 2-alpha kinase 2 HCV Hepatitis C Virus IFN interferon ISRE Interferon-stimulated response element KCS kinase-conserved sequence HCC hepatocellular carcinoma PEG-IFN-/RBV pegylated Interferon, and ribavirin SVR sustained virologic response NR non-responder GWAS genome-wide association studies UTR Untranslated Region PCR Polymerase Chain Reaction DMSO dimethyl sulfoxide SNPs single nucleotide polymorphisms PKR Promoter PCR SNPs HCV |
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