Characterization of the Interleukin-28B Gene rs12979860 C/T Polymorphism in Turkish Chronic Hepatitis C Patients and Healthy Individuals

Abstract

Background: Host genetic factors can affect the progress of hepatitis-C virus (HCV) infection. Interleukin-28B (IL28B) single nucleotide polymorphisms may play an important role in the clearance of HCV spontaneously or with treatment. Aims: The aim of our study was to evaluate the rate of IL28B genotypes in patients with Chronic Hepatitis-C (CHC) and healthy control subjects and to examine the characteristics of patients in each IL28B subgroup. Study Design: Case-control study. Methods: IL28B polymorphisms were genotyped by Polymerase Chain Reaction and Restriction Fragment Length Polymorphism (PCR-RFLP) in all subjects. Results: The mean age was 52.3±10.9 years (33% female) in the CHC patients and 52.5±11.5 years (39.1% female) in the healthy controls. The percentage of patients with a high baseline viral load (≥400,000 IU/mL) was higher in the CT group (69.8%) compared to the C/C (44.4%) and T/T (50%) groups (p=0.021). There was no significant difference in liver fibrosis and liver necroinflammation distribution among the CC, CT and TT genotypes with mild, moderate and severe groups (p=0.058 and p=0.791, respectively). Mean age, gender ratio, body mass index, viral load at baseline, rate of HCV genotypes, baseline ALT levels were not significantly different among the three IL28B subgroups (p>0.05). A significant increase was observed in the frequencies of IL28B rs12979860 TT genotypes in the CHC patients (20.6%) compared to the healthy control group (8.7%) (p=0.033). Conclusion: In the patients with chronic HCV-genotype 1b and 4 infections, the IL28B rs12979860 (C>T) gene polymorphism frequency of the TT genotype and T allele was higher than in healthy control subjects. This result indicates that the TT genotype may be more effective in the progression of HCV infection than other genotypes.

Keywords

• Chronic hepatitis C, gene polymorphism, IL28B, interleukins

References

1. 1. Aygen B. Hepatitis C. Turkiye Klinikleri J Int Med Sci 2006;2:21- 33.
2. 2. Aygen B. Kronik hepatit C’de tedavi ve izlem: In: Köksal İ, Leblebicioğlu H, editors. Kronik Hepatitlerin Tanı ve Tedavisinde Güncel Yaklaşımlar. 1st ed. Ankara: Bilimsel Tıp Yayınevi; 2009;223-33.
3. 3. Bozkurt I, Aygen B, Gökahmetoglu S, Yildiz O. Hepatitis C and Occult Hepatitis C Infection among Hemodialysis Patients from Central Anatolia. J Pure Appl Microbiol 2014:8:435-40.
4. 4. Bozkurt I, Aygen B, Gökahmetoglu S, Yildiz O. Frequency and epidemiologic characteristics of hepatitis C virus infection in patients receiving hemodialysis in our region. Klimik Journal 2012;25:19-23. [CrossRef]
5. 5. Mıstık R, Türkiye’de viral hepatit epidemiyolojisi: yayınların irdelenmesi. In: Tabak F, Balik I, Tekeli E, editors. Viral Hepatit 2007. 1st ed. Ankara: Oban Matbaası; 2007;9-50.
6. 6. Ökten A. Türkiye’de kronik hepatit, siroz ve hepatosellüler karsinoma etiyolojisi. Güncel Gastroenterol Derg 2003;7:187- 91.
7. 7. Gökahmetoğlu S, Bozdayı M, Özbakır Ö, Aygen B, Özbal Y, Soyuer I, Yildiz O. Hepatitis C virus genotypes detected in Erciyes University. J Turk Microbiol Soc 2007;37:35-8.
8. 8. Gökahmetoğlu S, Atalay MA, Kılınç A. Determination of the hepatitis C virus genotypes with “pyrosequencing” method. Erciyes Med J 2011;33:99-102.

9. 9. Aygen B, Yıldız O, Çaylan R, Köksal I, Saltoğlu N, Taşova Y, Leblebicioğlu H, et al. Combination of interferon induction therapy and ribavirin in chronic hepatitis C patients: results of a multicenter clinical trial. Viral Hepatitis Journal 2004;9:123-9.
10. 10. Yıldız O, Aygen B, Alp E, Gökahmetoğlu S, Soyuer I. Retrospective evaluation of different antiviral treatments for chronic hepatitis C infection. FLORA 2008;13:122-9.
11. 11. Aygen, B, Yıldız O, Bostancı F, Özbakır Ö, Gökahmetoğlu S, Patıroğlu TE. A comparison of interferon-alpha-2b induction therapy with interferon-alpha-2b plus ribavirin combination therapy for the treatment of chronic hepatitis C. FLORA 2004;9:189-99.
12. 12. Demiraslan H, Aygen B, Yıldız O, Soyuer I, Gökahmetoğlu S. A comparison of interferon α-2a plus ribavirin combination therapy with peginterferon α-2a plus ribavirin combination therapy for treatment of chronic hepatitis C. Viral Hepatitis Journal 2008;13:12-22.
13. 13. Rauch A, Kutalik Z, Descombes P, Cai T, Di Iulio J, Mueller T, et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome-wide association study. Gastroenterology 2010;138:1338-45. [CrossRef]
14. 14. Thomas DL, Thio CL, Martin MP, Qi Y, Ge D, O’Huigin C, et al. Genetic variation in IL28B and spontaneous clearance of hepatitis C virus. Nature 2009;461:798-801. [CrossRef]
15. 15. Fonseca-Coronado S, Vaughan G, Cruz-Rivera MY, Carpio-Pedroza JC, Ruiz-Tovar K, Ruiz-Pacheco JA, et al. Interleukin-28B genotyping by melt-mismatch amplification mutation assay PCR analysis using single nucleotide polymorphisms rs12979860 and rs8099917, a useful tool for prediction of therapy response in hepatitis C patients. J Clin Microbiol 2011;49:2706-10. [CrossRef]
16. 16. Lagging M, Askarieh G, Negro F, Bibert S, Soderholm J, Westin J, et al. Response prediction in chronic hepatitis C by assessment of IP-10 and IL28B-related single nucleotide polymorphisms. PLoS One 2011;6:e17232. [CrossRef]
17. 17. Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatmentinduced viral clearance. Nature 2009;461:399-401. [CrossRef]
18. 18. Grebely J, Petoumenos K, Hellard M, Matthews GV, Suppiah V, Applegate T, et al. Potential role for interleukin-28B genotype in treatment decision-making in recent hepatitis C virus infection. Hepatology 2010;52:1216-24. [CrossRef]
19. 19. Sporea I, Popescu A , Curescu M, Sirli R, Dan I, Goldis A, et al. The correlation of Il28B Genotype with sustained virologic response in Romanian patients with chronic hepatitis C. Hepat Mon 2011;11:975-9. [CrossRef]
20. 20. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB; American Association for Study of Liver Diseases. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 Practice guideline by the American Association for the Study of Liver Diseases. Hepatology 2011;54:1433-44. [CrossRef]
21. 21. Omata M, Kanda T, Yu ML, Yokosuka O, Lim SG, Jafri W, et al. APASL consensus statements and management algorithms for hepatitis C virus infection. Hepatol Int 2012;6:409-35. [CrossRef]
22. 22. Ishak K, Baptisa A, Bianchi L, Callea F, De Groote J, Gudat F, et al. Histological grading and staging of chronic hepatitis. J Hepatol 1995;22:696-9. [CrossRef]
23. 23. Falleti E, Bitetto D, Fabris C, Cussigh A, Fornasiere E, Cmet S, et al. Role of interleukin 28B rs12979860 C/T polymorphism on the histological outcome of chronic hepatitis C: relationship with gender and viral genotype. J Clin Immunol 2011;31:891-9. [CrossRef]
24. 24. El Awady MK, Noha El Din NGB, Tabll A, El Hosary Y, Abdel Aziz AO, El Khayat H, et al. IL28B polymorphism and cytomegalovirus predict response to treatment in Egyptian HCV type 4 patients. World J Gastroenterol 2013;19:290-8. [CrossRef]
25. 25. Tozun N, Ozdogan OC, Cakaloglu Y, İdilman R, Karasu Z, Akarca U, et al. Nationwide prevalence study and risk factors for hepatitis A, B, C and D infections in Turkey. Hepatology 2010;52(Suppl 1):697.
26. 26. Özer B, Seydaoğlu G, Özşahın AK, Demırhındı H. Risk factors for higher anti-HCV positivity in a border city in southern Turkey with unique population characteristics. Turk J Gastroenterol 2012;23:574-9.
27. 27. Yildirim B, Barut S, Bulut Y, Yenişehirli G, Ozdemir M, Cetin I, et al. Seroprevalence of hepatitis B and C viruses in the province of Tokat in the Black Sea region of Turkey: A population-based study. Turk J Gastroenterol 2009;20:27-30.
28. 28. Simsek H, Alp A, Yilmaz B, Balabana YH, Altun B, Uzun O, et al. The genotype frequencies of IL28B polymorphisms (rs12979860, rs8099917) among Turkish patients with hepatitis C. Eur J Gastroenterol Hepatol 2012;24:1113-6. [CrossRef]
29. 29. Manolio TA. Genomewide association studies and assessment of the risk of disease. N Engl J Med 2010;363:166-76. [CrossRef]
30. 30. Kelly C, Klenerman P, Barnes E. Interferon lambdas: the next cytokine storm. Gut 2011;60:1284-93. [CrossRef]
31. 31. El-Awady MK, Mostafa L, Tabll AA, Abdelhafez TH, El Din NGB, Zayed N, et al. Association of IL28B SNP with progression of Egyptian HCV genotype 4 patients to end stage liver disease. Hepat Mon 2012;12:271-7. [CrossRef]
32. 32. Liao XW, Ling Y, Li XH, Han Y, Zhang SY, Gu LL, et al. Association of genetic variation in IL28B with hepatitis C treatmentinduced viral clearance in the Chinese Han population. Antivir Ther 2011;16:141-7. [CrossRef]
33. 33. da Silva Conde SR, Soares Monteiro JC, Silva Dos Santos BT, Fonseca Filgueiras NK, de Almeida Lins PA, Bonfim Freitas F, et al. SNP rs8099917 in gene IL28B might be associated with risk of chronic infection by HCV but not with response to treatment. Biomed Res Int 2014;2014:748606. [CrossRef]
34. 34. Ruiz-Extremera A, Munoz-Gamez JA, Salmeron-Ruiz MA, de Rueda PM, Quiles-Perez R, Gila-Medina A, Casado J, et al. Genetic variation in interleukin 28B with respect to vertical transmission of hepatitis C virus and spontaneous clearance in HCVinfected children. Hepatology 2011;53:1830-8. [CrossRef]
35. 35. Fabris C, Falleti E, Cussigh A, Bitetto D, Fontanini E, Bignulin S, et al. IL-28B rs12979860 C/T allele distribution in patients with liver cirrhosis: role in the course of chronic viral hepatitis and the development of HCC. J Hepatol 2011;54:716-22. [CrossRef]