Interleukin 28A.rs12980602 and interleukin 28B.rs8103142 genotypes could be protective against HCV infection among Egyptians
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Previous studies showed that interleukin (IL)-28B gene polymorphisms were associated with hepatitis C Virus (HCV) infection and treatment outcomes. We tested whether single-nucleotide polymorphisms (SNPs) in IL-28A and IL-28B are associated with HCV infection among Egyptians with HCV genotype 4 infections. We enrolled 144 chronic HCV patients, 72 spontaneously resolved HCV subjects, and 69 healthy controls. Four SNPs in IL-28A and IL-28B genes (IL-28A.rs12980602, IL-28B.rs12979860, IL-28B.rs8099917, and IL-28B.rs8103142) were genotyped. The most frequent IL-28B haplotype “TCT” was significantly more frequent in HCV-infected subjects than in HCV negative subjects (62.2% vs. 48.6%, respectively; p = 0.005). The frequency of IL-28A.rs12980602 “T” allele was significantly higher than the “C” allele in healthy controls compared to HCV-infected subjects (p < 0.001) with the “TT” genotype significantly higher in healthy controls compared to HCV-infected subjects (p < 0.001) with no association with viral load (p = 0.11) among chronically infected subjects. The results, also, confirmed the previous role of IL-28B SNPs in predicting HCV infection outcome. Importantly, IL-28B.rs8099917 “TT” genotype was significantly associated with low viral load in HCV-infected subjects, while the remaining three SNPs did not. The three IL-28B SNPs were in linkage disequilibrium (D′ > 0.68; r2 > 0.43) for all comparisons in HCV patients, while there was no linkage disequilibrium of IL-28A polymorphisms and the three IL-28B SNPs. In conclusion, IL-28A.rs12980602 and IL-28B.rs8103142 TT genotype could be protective against HCV infection. Also, IL-28B.rs12979860, IL-28B.rs8099917, and IL-28B.rs8103142 SNPs predicted the outcome of HCV infection among genotype-4-infected Egyptians. Moreover, IL-28B.rs8099917 SNP affected the viral load in chronic HCV patients.
KeywordsHCV Single-nucleotide polymorphism IL-28A IL-28B IFN-λ
We would like to thank Dr. Nabiel Mikhail and Enas S. Aziz (Egyblood) for their technical help with the data. We thank Mrs. Hoayda M. Ahmed and Dr. Mohamed Abdel-Samee (from the NLI) for their assistance with sample collection and enrollment of the subjects. We particularly appreciate Dr. Gehan Galal (Director of Egyblood R&D Department), Dr. Nelly Sedky, and Dr. Hala Hussein (previous Egyblood CEOs,) for their support throughout the conduct of the study.
This study was supported by the European Union 6th Framework Program contract no. 0374435 to the HEPACIVAC consortium and by the European Union 7th Framework Program contract no. 260844 to the HEPACUTE consortium.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
Research involving human participants and/or animals
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committees and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study protocol was approved by the NLI Institutional Review Board.
Informed consent was obtained from all participants included in the study.
- 1.Collaborators TPOH. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study. Lancet Gastroenterol Hepatol. 2017;2(3):161–76.Google Scholar
- 2.WHO. Hepatitis C [fact sheet]. Geneva: World Health Organization; 2016.Google Scholar
- 4.Ministry of Health E, El-Zanaty and Associates, Egypt and ICF International. Egypt Health Issues Survey. Cairo, Egypt and Rockville: Ministry of Health and ICF International; 2015. p. 2015.Google Scholar
- 5.Simmonds P, Holmes EC, Cha TA, Chan SW, McOmish F, Irvine B, et al. Classification of hepatitis C virus into six major genotypes and a series of subtypes by phylogenetic analysis of the NS-5 region. J Gen Virol. 1993;74(Pt 11):2391–9.Google Scholar
- 6.El-Zayadi A, Selim O, Dabbous HK, Bianchi F. High frequency of smooth muscle antibodies (SMA) among HCV positive chronic liver disease patients in Egypt. J Egypt Public Health Assoc. 1994;69(3–4):205–11.Google Scholar
- 8.Abdelwahab S, Rewisha E, Hashem M, Sobhy M, Galal I, Allam WR, et al. Risk factors for hepatitis C virus infection among Egyptian healthcare workers in a national liver diseases referral centre. Trans R Soc Trop Med Hyg. 2012;106(2):98–103. https://doi.org/10.1016/j.trstmh.2011.10.003.Google Scholar
- 9.El-Zanaty FWA. Egypt demographic and health survey 2008. Cairo: Ministry of Health, El-Zanaty and Associates and Macro International; 2009. p. 431.Google Scholar
- 11.MHP, El-Zanaty F, ICF. Ministry of Health and Population [Egypt], El-Zanaty and Associates [Egypt], ICF International, Egypt health issues survey 2015. Cairo, Rockville: Ministry of Health and Population, ICF International; 2015.Google Scholar
- 16.Thomas DL, Astemborski J, Rai RM, Anania FA, Schaeffer M, Galai N, et al. The natural history of hepatitis C virus infection: host, viral, and environmental factors. JAMA. 2000;284(4):450–6.Google Scholar
- 18.Balagopal A, Thomas DL, Thio CL. IL28B and the control of hepatitis C virus infection. Gastroenterology. 2010;139(6):1865–76.Google Scholar
- 19.McFarland AP, Horner SM, Jarret A, Joslyn RC, Bindewald E, Shapiro BA, et al. The favorable IFNL3 genotype escapes mRNA decay mediated by AU-rich elements and hepatitis C virus-induced microRNAs. Nat Immunol. 2014;15(1):72–9.Google Scholar
- 27.Brand S, Beigel F, Olszak T, Zitzmann K, Eichhorst ST, Otte JM, et al. IL-28A and IL-29 mediate antiproliferative and antiviral signals in intestinal epithelial cells and murine CMV infection increases colonic IL-28A expression. Am J Physiol Gastrointest Liver Physiol. 2005;289(5):G960–8. https://doi.org/10.1152/ajpgi.00126.2005.Google Scholar
- 28.Ank N, West H, Bartholdy C, Eriksson K, Thomsen AR, Paludan SR. Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J Virol. 2006;80(9):4501–9. https://doi.org/10.1128/jvi.80.9.4501-4509.2006.Google Scholar
- 31.Diegelmann J, Beigel F, Zitzmann K, Kaul A, Goke B, Auernhammer CJ, et al. Comparative analysis of the lambda-interferons IL-28A and IL-29 regarding their transcriptome and their antiviral properties against hepatitis C virus. PLoS One. 2010;5(12):e15200. https://doi.org/10.1371/journal.pone.0015200.Google Scholar
- 32.Ge D, Fellay J, Thompson AJ, Simon JS, Shianna KV, Urban TJ, et al. Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance. Nature. 2009;461(7262):399–401.Google Scholar
- 34.Tanaka Y, Nishida N, Sugiyama M, Kurosaki M, Matsuura K, Sakamoto N, et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet. 2009;41(10):1105–9.Google Scholar
- 35.Kurbanov F, Abdel-Hamid M, Latanich R, Astemborski J, Mohamed M, Mikhail NM, et al. Genetic polymorphism in IL28B is associated with spontaneous clearance of hepatitis C virus genotype 4 infection in an Egyptian cohort. J Infect Dis. 2011;204(9):1391–4.Google Scholar
- 36.Pasha HF, Radwan MI, Hagrass HA, Tantawy EA, Emara MH. Cytokines genes polymorphisms in chronic hepatitis C: impact on susceptibility to infection and response to therapy. Cytokine. 2013;61(2):478–84.Google Scholar
- 37.Derbala M, Rizk NM, Al-Kaabi S, John A, Sharma M, El-dweik N, et al. The predictive value of IL28B rs12979860, rs11881222 and rs8099917 polymorphisms and IP-10 in the therapeutic response of Egyptian genotype 4 patients. Virology. 2013;444(1–2):292–300.Google Scholar
- 38.Pedergnana V, Abdel-Hamid M, Guergnon J, Mohsen A, Le Fouler L, Theodorou I, et al. Analysis of IL28B variants in an Egyptian population defines the 20 kilobases minimal region involved in spontaneous clearance of hepatitis C virus. PLoS One. 2012;7(6):e38578.Google Scholar
- 39.Asselah T. A revolution in HCV treatment with direct-acting antivirals: from non-response to eradication. J Hepatol. 2012;57(2):455–7.Google Scholar
- 40.Asselah T, De Muynck S, Broet P, Masliah-Planchon J, Blanluet M, Bieche I, et al. IL28B polymorphism is associated with treatment response in patients with genotype 4 chronic hepatitis C. J Hepatol. 2012;56(3):527–32.Google Scholar
- 48.Dolganiuc A, Kodys K, Marshall C, Saha B, Zhang S, Bala S, et al. Type III interferons, IL-28 and IL-29, are increased in chronic HCV infection and induce myeloid dendritic cell-mediated FoxP3+ regulatory T cells. PLoS One. 2012;7(10):e44915. https://doi.org/10.1371/journal.pone.0044915.Google Scholar
- 49.Suppiah V, Moldovan M, Ahlenstiel G, Berg T, Weltman M, Abate ML. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat Genet. 2009;41:1100–4.Google Scholar
- 50.Urban TJ, Thompson AJ, Bradrick SS, Fellay J, Schuppan D, Cronin KD, et al. IL28B genotype is associated with differential expression of intrahepatic interferon-stimulated genes in patients with chronic hepatitis C. Hepatology (Baltimore, MD). 2010;52(6):1888–96. https://doi.org/10.1002/hep.23912.Google Scholar
- 51.Smith KR, Suppiah V, O'Connor K, Berg T, Weltman M, Abate ML, et al. Identification of improved IL28B SNPs and haplotypes for prediction of drug response in treatment of hepatitis C using massively parallel sequencing in a cross-sectional European cohort. Genome Med. 2011;3(8):57. https://doi.org/10.1186/gm273.Google Scholar
- 53.Di Marco V, Bronte F, Calvaruso V, Capra M, Borsellino Z, Maggio A, et al. IL28B polymorphisms influence stage of fibrosis and spontaneous or interferon-induced viral clearance in thalassemia patients with hepatitis C virus infection. Haematologica. 2012;97(5):679–86. https://doi.org/10.3324/haematol.2011.050351.Google Scholar
- 55.Yu F, Wang Y, Yuan S, Ma J, Ma N, Zhang X, et al. Association between gene polymorphisms of IL-28 and response to lamivudine in Chinese rural patients with chronic hepatitis B. Scandinavian Journal of Gast Roenterology. 2013;48:745–51.Google Scholar
- 56.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(1338–1345):1345.e1331–7.Google Scholar
- 58.About F, Oudot-Mellakh T, Niay J, Rabiéga P, Pedergnana V, Duffy D. Impact of IL28B, APOH and ITPA polymorphisms on efficacy and safety of TVRor BOC-based triple therapy in treatment-experienced HCV-1 patients with compensated cirrhosis from the ANRS CO20-CUPIC study. PLoS One. 2015;10. https://doi.org/10.1371/journal.pone.0145105.
- 59.Barreiro P, Vispo E, Poveda E, Fernández-Montero JV, Soriano V. Hepatitis C therapy: highlights from the 2012 annual meeting of the European Association for the Study of the liver. Clin Infect Dis. 2013;56. https://doi.org/10.1093/cid/cis915.
- 60.Calisti G, Tavares A, Macartney MJ, McCormick A, Labbett W, Jacobs M. IL28B genotype predicts response to chronic hepatitis C triple therapy with telaprevir or boceprevir in treatment naïve and treatment-experienced patients other than prior partial- and null-responders. Spring 2015;4. doi: https://doi.org/10.1186/s40064-015-1137-x.
- 61.D’Offizi G, Cammà C, Taibi C, Schlag M, Palma M, Demasi R. Clinical and virological predictors of sustained response with an interferon-based simeprevir regimen for patients with chronic genotype 1 hepatitis C virus infection. New Microbiol 2017;40(1):19–26.Google Scholar
- 62.Holmes JA, Desmond PV, Thompson AJ. Does IL28B genotyping still have a role in the era of direct-acting antiviral therapy for chronic hepatitis C infection? J Viral Hepat 2012;19(10):677–84.Google Scholar
- 63.Akuta N, Sezaki H, Suzuki F, Fujiyama S, Kawamura Y, Hosaka T. Retreatment efficacy and predictors of ledipasvir plus sofosbuvir to HCV genotype 1 in Japan. J Med Virol 2017;89(2):284–90.Google Scholar
- 66.Halfon P, Bourliere M, Ouzan D, Maor Y, Renou C, Wartelle C, et al. A single IL28B genotype SNP rs12979860 determination predicts treatment response in patients with chronic hepatitis C genotype 1 virus. Eur J Gastroenterol Hepatol. 2011;23(10):931–5. https://doi.org/10.1097/MEG.0b013e328349d0ef.Google Scholar