Abstract
Cytokines play a central role in regulating the anti-viral responses against hepatitis C virus (HCV). The objective of this study were to evaluate the effect of proinflammatory cytokines (IL-18 − 607 C/A, rs 1946518; IL-18 − 137 G/C, rs 187283; INF-γ + 874 T/A, rs 240561), SNPs, and the anti-inflammatory cytokine (IL-10 + 1082 G/A, rs 1800896) SNPs on the risk of development of hepatic cirrhosis in Egyptian patients and to evaluate the combined effect of the polymorphic variants that show an interrelation with the risk of hepatic cirrhosis. The study included 63 chronic HCV patients. The patients were stratified into two groups. Group 1 consisted of 33 cirrhotic chronic hepatitis C patients while the second group consisted of 30 non-cirrhotic chronic hepatitis C patients that were taken as a control group. Genotyping of IFN-γ (+ 874 T/A) and IL-10 (− 1082 G/A) SNPs was performed by allele-specific PCR technique (AS-PCR). Genotyping of IL-18 (− 607 C/A) and IL-18 (− 137 G/C) SNPs was determined by PCR-RFLP technique. Analysis of IFN-γ (+ 874 T/A) SNP revealed that the T allele and the TT genotype were significantly higher in cirrhotic patients’ group compared to non-cirrhotic group (P < 0.001 and P = 0.004, respectively). Analysis of IL-10 (− 1082 G/A) SNP revealed that the A allele and AA genotype were significantly higher in the cirrhotic patients’ group (P = 0.001 and P = 0.047, respectively). Regression analysis revealed that IFN-γ Hi/IL-10 Lo combined genotypes were significantly higher in liver cirrhosis patients compared to non-cirrhotic patients (P = 0.002). INF-γ (+ 874 T/A) and IL-10 (+ 1082 G/A) SNPs might be associated with occurrence of hepatic cirrhosis in chronic HCV Egyptian patients.
Similar content being viewed by others
References
Aaron PT, Hashem BE, Fasiha K (2017) Global epidemiology and burden of HCV infection and HCV-related diseases. Nat Rev Gastroenterol Hepatol 14:122–132
Abbas Z, Moatter T, Hussainy A, Jafri W (2005) (2005): Effect of cytokine gene polymorphism on histological activity index, viral load and response to treatment in patients with chronic hepatitis C genotype 3. World J Gastroenterol 11:6656–6661
Afzal MS, Tahir S, Salman A, Baig TA, Shafi T, Us N et al (2011) Analysis of interlukin-10 gene polymorphisms and hepatitis c susceptibility in Pakistan. J Infect Dev Ctries 5(6):473–479
Avise JC (2004) Molecular markers natural history and evolution. Chapman and Hall, New York 511PP,171 bp
Biolo G, Amoroso A, Savoldi S, Bisutti A, Martone M, Pirulli D et al (2006) Association of interferon-gamma +874A polymorphism with reduced long-term inflammatory response in haemodialysis patients. Nephrol Dial Transplant 21:1317–1322
Bouzgarou N, Hassen E, Bahri O, Gabbouj S, Mami NB, Triki H (2011) Combined effect of pro- and anti-inflammatory cytokine gene polymorphisms on susceptibility to liver cirrhosis in Tunisian HCV-infected patients. Hepatol Int 5:681–687
Bouzgarrou N, Hassan E, Farahat K, Bahri O, Gabbouj S, Maamouri N (2009) Combined analysis of interferon-γ and interlukin-10 gene polymorphisms and chronic hepatitis c severity. Hum Immunol 70:230–236
Castera L, Le Bail B, Roudot-Thoraval F et al (2009) Early detection in routine clinical practice of cirrhosis and esophageal varices in chronic hepatitis C: comparison of transient electrography (Fibroscan) with standard laboratory tests and non invasive scores. J Hepatol 50:59–68
da Silva NM, Germano FN, Vidalis-Braz BM, Carmo-Zanella RD, dos Santos DM, Lobato R (2014) Polymorphism of IL-10 gene in patients infected with HCV under antiviral treatment in southern Brazil. Cytokine 73(2):253–257
Dai CY, Chuang WL, Hsieh MY, Lee LP, Hou NJ, Chen SC (2006) Polymorphism of interferon-gamma gene at position +874 and clinical characteristics of chronic hepatitis C. Transl Res 148(3):128–133
Doss R, Shiha G, Hassany M, Soliman R, Fouad R, Khairy M et al (2015) Sofosbuvir plus Ribavirin for treating Egyptian patients with hepatitis C genotype 4. J Hepatol 63:581–585
Falasca K, Ucciferri C, Dalessandro M, Zingariello P, Mancino P, Petrarca C et al (2006) Cytokine patterns correlate with liver damage in patients with chronic hepatitis B and C. Ann Clin Lab Sci 36:144–150
Falleti E, Fabris C, Toniutto P, Fontanini E, Cussigh A, Caldato M, Rossi E, Bitetto D, Minisini R, Smirne C, Pirisi M (2007) Genetic polymorphisms of inflammatory cytokines and liver fibrosis progression due to recurrent hepatitis C. J Interf Cytokine Res 27:239–246
Folwaczny M, Glas J, Torok HP, Paschos E, Bauer B, Limbersky O (2005) Polymorphisms of interleukin-18 gene in periodontology Patients. J Clin Periodontol 32:530
Gao QJ, Liu DW, Zxhang SY, Jia M, Wang LM, Wu LM et al (2009) Polymorphisms of some cytokines and chronic hepatitis B and C virus infection. World J Gastroenterol 15(44):5610–5619
Gaudet M, Ag F, Beritognolo I, Sabatti M (2009) Allele specific PCR SNP genotyping. Methods Mol Biol 587:415–424
Gaurav D, Anita C (2009) To determine the polymorphism of tumor necrosis factor-alpha and interleukin-10 genes in chronic hepatitis C patients. Indian J Virol 20:1 Print ISSN: 0970-2822. Online ISSN: 0974-0120
Giedraitis V, He B, Huang WX, Hillert J (2001) Cloning and mutation analysis of the human IL-18 promoter: a possible role of polymorphisms in expression regulation. J Neuroimmunol 112:146–152
Gigi E, Raptopoulou-Gigi M, Kalogeridis A, Masiou S, Orphanou E, Vrettou E et al (2008) Cytokine mRNA expression in hepatitis C virus infection: the predominance in patients with chronic hepatitis C and Th1-Th2 cytokine profile in subjects with self-limited disease. J Virol Hepat 15:145–154
Kakizaki S, Takagi H, Yamazaki Y, Sohara N, Sato K, Nagamine T, Masatomo M (2006) Different outcomes of nosocomial infection with hepatitis C virus from the same origin. World J Gastroenterol 12:659–661
Kawakami Y, Nabeshima S, Furusyo N, Sawayama Y, Hayashi J, Kashiwagi S (2000) Increased frequency of interferon-gamma-producing peripheral blood CD4? T cells in chronic hepatitis C virus infection. Am J Gastroenterol 95:3670–3673
Mandour M, Nemr N, Kishk R, Ahmed E (2014) Impact of the IL-18 gene polymorphism in response to antiviral therapy in chronic HCV genotype 4 patients. Rev Soc Bras Med Trop 47(2):137–142
Manohar K, Suneetha PV, Skriti PNT, Goupta C, Hissar S et al (2009) Association of IL-18 promoter polymorphism with liver disease severity in HCV-infected patients. Hepatol Int 3:371–377
Minton EJ, Smillie D, Smith P et al (2005) Clearance of hepatitis C virus is not associated with single nucleotide polymorphisms in the IL-1, -6, or -10 genes. Hum Immunol 66:127–132
Moudi B, Heidari Z, Mahmoudzadeh-Sagheb H, Hashmi M, Farrokh P (2016) Association between IL-10 gene promoter polymorphisms (-592 A/C, -819 T/C,-1082 A/G) and susceptibility to HBV infection in an Iranian population. Hepat Mon 16(2):e32427
Nelson DR, Lauwers GY, Lau JY, Davis GL (2000) Interleukin 10 treatment reduces fibrosis in patients with chronic hepatitis C: a pilot trial of interferon nonresponders. Gastroenterology 118:655–660
Neuman MG, Benhamou JP, Marcellin P, Valla D, Malkiewicz IM, Kat GG, Trepo C, Bourliere M, Cameron RG, Cohen L, Morgan M, Schmilovitz-Weiss H, Ben-Ari Z (2007) Cytokine–chemokine and apoptotic signatures in patients with hepatitis C. Transl Res 149:126–136
Novak N, Kruse S, Potreck J, Maintz L, Jenneck C, Weidinger S, Fimmers R, Bieber T (2005) Single nucleotide polymorphisms of the IL-18 gene are associated with atopic eczema. J Allergy Clin Immunol 115:828–833
Oleksyk TK, Thio CL, Al T et al (2005) Single nucleotide polymorphisms and haplotypes in the IL-10 region associated with HCV clearance. Genes Immun 6:347–357
Pasha HF, Radwan MI, Hagrass HA, Tantawy HA, Emara MH (2013) Cytokines genes polymorphisms in chronic hepatitis c:impact on susceptibility to infection and response to therapy. Cytokine 61(2):478–484
Poyrad T, Ratziu V, Benmanov Y et al (2000) Fibrosis in patients with chronic hepatitis C: detection and significance. Semin Liv Dis 20:47–55
Sun MH, Han XC, Jia MK, Jiang WD, Wang M, Zhang H et al (2005) Expressions of inducible nitric oxide synthase and matrix metalloproteinase-9 and their effects on angiogenesis and progression of hepatocellular carcinoma. World J Gastroentrol 11:5931–5937
Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV (1997) An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet 24:1–8
Waked I, Doss W, El-Sayed MH, Estes C, Razavi H, Shiha G, et al. (2014): The current and future disease burden of chronic hepatitis C virus infection in Egypt
Wang XH, Netski DM, Astemborski J, Mehta SH, Torbenson MS, Thomas DL, Ray SC (2007) Progression of fibrosis during chronic hepatitis C is associated with rapid virus evolution. J Virol 81:6513–6522
Wu Z, Sun Y, Zhu S, Tang S, Liu C, Qin W (2016) Association of interferon gamma +874 T/A polymorphism and leukemia risk: a meta-analysis. Medicine 95(12):e3129
Zhang LJ, Wang XZ (2006) Interleukin-10 and chronic liver disease. World J Gastroenterol 12:1681–1685
Acknowledgments
We would like express our deepest gratitude for Assistant Professor Dr. Dina Mehaney (Assistant professor of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University) for her help in the RFLP/PAGE analysis.
Funding
This work was not funded by any organization.
Author information
Authors and Affiliations
Contributions
The authors contributed equally in all aspects of the study.
Corresponding author
Ethics declarations
Ethical approval
The present case control study was conducted in Beni-Suef University Hospital. All patients and control subjects were notified of the purpose of the study, and their consent was obtained, and the study was approved by the local ethics committee. All procedures accomplished in the study concerning human participants were in accordance with the institutional ethical standards and with the 1964 Helsinki Declaration and its later amendments in 2004.
Conflict of interest
The authors declare that there are no conflicts of interest.
Additional information
Declaration: The manuscript has not been published elsewhere and has not been submitted simultaneously for publication elsewhere.
Rights and permissions
About this article
Cite this article
Mohamed, R.A., ELfeki, M.A., Fathy, W. et al. The genetic association of cytokine genes, single nucleotide polymorphisms, and the incidence of liver cirrhosis in chronic hepatitis C Egyptian patients. Comp Clin Pathol 27, 61–70 (2018). https://doi.org/10.1007/s00580-017-2553-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00580-017-2553-9