ANALYSIS AND ASSOCIATION OF POLYMORPHISM IN TLR-3 GENE WITH LIVER COMPLICATIONS IN CHRONIC HCV PAKISTANI PATIENTS
Main Article Content
Keywords
TLR-3 gene, allele polymorphism, HCV infection, susceptibility, resistance, fibrosis
Abstract
Hepatitis C virus (HCV) causes a significant health challenge in Pakistan. Previous research has suggested a correlation between polymorphisms in the TLR-3 gene and HCV infection. This study is aimed to analyze TLR-3 gene polymorphism in Pakistani individuals with chronic HCV infection and their association with liver complications. The study analyzes the exon-4 region of the TLR-3 gene through sequencing and clinical parameters in 110 chronically HCV-infected patients with various liver complications. A total of 120 healthy subjects are also included for comparison of TLR-3 polymorphism. The distribution of the TLR-3 SNP rs3775290 genotypes as CC (48.7%), CT (40.9%), and TT (10.4%), demonstrates a statistically significant association in both genotype and allele frequencies within the study population. Notably, the CC genotype is more frequently observed in a comparative healthy group (63%), while the CT genotype is predominant in HCV-infected individuals (56%), and the TT genotype is most prevalent in patients with liver fibrosis (43%). Genotype distributions for both SNPs were consistent with Hardy-Weinberg expectations. Furthermore, the study found that higher HCV viral loads and more advanced stages of liver fibrosis correlated with specific rs3775290 genotypes.
It is concluded that the CC genotype of TLR-3 rs3775290 is prevalent and associated with a potential protective effect against chronic HCV infection in the study population. Moreover, the CT genotype appears associated to HCV chronicity, and the TT genotype with the progression to advanced liver disease. The CT and TT genotypes are also associated with elevated viral load and increased fibrosis severity. Further large-scale investigations across diverse regions of Pakistan are required to comprehensively understand the role and association of TLR-3 SNPs with susceptibility to HCV infection and disease progression.
References
2. Suhail, M., et al., Role of hepatitis c virus in hepatocellular carcinoma and neurological disorders: an overview. Front Oncol, 2022. 12: p. 913231.
3. Taherkhani, R. and F. Farshadpour, Global elimination of hepatitis C virus infection: Progresses and the remaining challenges. World J Hepatol, 2017. 9(33): p. 1239-1252.
4. Sebastiani, G., K. Gkouvatsos, and K. Pantopoulos, Chronic hepatitis C and liver fibrosis. World J Gastroenterol, 2014. 20(32): p. 11033-53.
5. Al Kanaani, Z., et al., The epidemiology of hepatitis C virus in Pakistan: systematic review and meta-analyses. R Soc Open Sci, 2018. 5(4): p. 180257.
6. Diamond, M.S. and T.-D. Kanneganti, Innate immunity: the first line of defense against SARS-CoV-2. Nature Immunology, 2022. 23(2): p. 165-176.
7. Li, D. and M. Wu, Pattern recognition receptors in health and diseases. Signal Transduction and Targeted Therapy, 2021. 6(1): p. 291.
8. Fore, F., et al., TLR10 and Its Unique Anti-Inflammatory Properties and Potential Use as a Target in Therapeutics. Immune Netw, 2020. 20(3): p. e21.
9. Vijay, K., Toll-like receptors in immunity and inflammatory diseases: Past, present, and future. Int Immunopharmacol, 2018. 59: p. 391-412.
10. Kiziltas, S., Toll-like receptors in pathophysiology of liver diseases. World J Hepatol, 2016. 8(32): p. 1354-1369.
11. Gale, M., Jr., The role of innate immunity in chronic hepatitis C viral infection. Gastroenterol Hepatol (N Y), 2007. 3(9): p. 683-4.
12. Medvedev, A.E., Toll-like receptor polymorphisms, inflammatory and infectious diseases, allergies, and cancer. J Interferon Cytokine Res, 2013. 33(9): p. 467-84.
13. Habibabadi, H.M., et al., Association of TLR3 single nucleotide polymorphisms with susceptibility to HTLV-1 infection in Iranian asymptomatic blood donors. Rev Soc Bras Med Trop, 2020. 53: p. e20200026.
14. Mosaad, Y.M., et al., Association between Toll-Like Receptor 3 (TLR3) rs3775290, TLR7 rs179008, TLR9 rs352140 and Chronic HCV. Immunol Invest, 2019. 48(3): p. 321-332.
15. Tian, H., et al., Association of TLR3 gene 1377C/T (rs3775290) and TLR7 gene C/G (rs3853839) polymorphism with hand, foot, and mouth disease caused by human enterovirus 71 infection susceptibility and severity in the Chinese Han population: A meta-analysis of case-control studies. Medicine (Baltimore), 2022. 101(27): p. e29758.
16. El-Bendary, M., et al., The association of single nucleotide polymorphisms of Toll-like receptor 3, Toll-like receptor 7 and Toll-like receptor 8 genes with the susceptibility to HCV infection. Br J Biomed Sci, 2018. 75(4): p. 175-181.
17. Sghaier, I., et al., TLR3 and TLR4 SNP variants in the liver disease resulting from hepatitis B virus and hepatitis C virus infection. Br J Biomed Sci, 2019. 76(1): p. 35-41.
18. Geng, P.L., et al., Toll-Like Receptor 3 is Associated With the Risk of HCV Infection and HBV-Related Diseases. Medicine (Baltimore), 2016. 95(21): p. e2302.
19. Valverde-Villegas, J.M., et al., Endosomal toll-like receptor gene polymorphisms and susceptibility to HIV and HCV co-infection - Differential influence in individuals with distinct ethnic background. Hum Immunol, 2017. 78(2): p. 221-226.
20. Mooneyhan, E., et al., Hepatitis C prevalence and elimination planning in Pakistan, a bottom-up approach accounting for provincial variation. J Viral Hepat, 2023. 30(4): p. 345-354.
21. Shaikh, O.A., et al., Pakistan’s struggle to tame hepatitis: an ongoing threat. IJS Global Health, 2023. 6(2): p. e123.
22. Negro, F., Natural History of Hepatic and Extrahepatic Hepatitis C Virus Diseases and Impact of Interferon-Free HCV Therapy. Cold Spring Harb Perspect Med, 2020. 10(4).
23. Ferreira, A.R., et al., Hepatitis C Virus: Evading the Intracellular Innate Immunity. J Clin Med, 2020. 9(3).
24. Coppola, N., et al., Role of genetic polymorphisms in hepatitis C virus chronic infection. World J Clin Cases, 2015. 3(9): p. 807-22.
25. Mogensen, T.H., Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev, 2009. 22(2): p. 240-73, Table of Contents.
26. Duan, T., et al., Toll-Like Receptor Signaling and Its Role in Cell-Mediated Immunity. Front Immunol, 2022. 13: p. 812774.
27. Fischer, J., et al., Polymorphisms in the Toll-like receptor 3 (TLR3) gene are associated with the natural course of hepatitis B virus infection in Caucasian population. Scientific Reports, 2018. 8(1): p. 12737.
28. Kayesh, M.E.H., M. Kohara, and K. Tsukiyama-Kohara, Toll-like Receptor Response to Hepatitis C Virus Infection: A Recent Overview. Int J Mol Sci, 2022. 23(10).
29. Guedes de Sá KS, A.E., Conde SRSDS, Queiroz MAF, Cayres-Vallinoto IMV, Ishak R, Vallinoto ACR., Intrahepatic TLR3 and IFNL3 Expressions Are Associated with Stages of Fibrosis in Chronic Hepatitis C. viruses, 2021. 13(6): p. 1103.
30. Tang, X., et al., The scientific progress and prospects of hepatitis C research from 2013 to 2022. Am J Transl Res, 2022. 14(11): p. 7806-7819.
31. Wang, N., et al., Toll-like receptor 3 mediates establishment of an antiviral state against hepatitis C virus in hepatoma cells. J Virol, 2009. 83(19): p. 9824-34.
32. Youssef M. Mosaad, S.S.M., Raghda E. Farag, Zakeria F. Lotfy & Hosam E. AbdelTwab, Association between Toll-Like Receptor 3 (TLR3) rs3775290, TLR7 rs179008, TLR9 rs352140 and Chronic HCV. Immunological Investigations, 2018.
33. Zayed, R.A., et al., Association of Toll-Like Receptor 3 and Toll-Like Receptor 9 Single Nucleotide Polymorphisms with Hepatitis C Virus Infection and Hepatic Fibrosis in Egyptian Patients. Am J Trop Med Hyg, 2017. 96(3): p. 720-726.
34. Mohammed, K.I., et al., Expression of Toll like receptors 3 & 7 in peripheral blood from patients with chronic hepatitis C virus infection and their correlation with interferon-alpha. Egypt J Immunol, 2013. 20(1): p. 13-22.
35. Yuki, N., et al., Involvement of Differential Relationship between HCV Replication and Hepatic PRR Signaling Gene Expression in Responsiveness to IFN-Based Therapy. Hepat Res Treat, 2013. 2013: p. 917261.
36. Howell, J., et al., Toll-like receptor 3 and 7/8 function is impaired in hepatitis C rapid fibrosis progression post-liver transplantation. Am J Transplant, 2013. 13(4): p. 943-953.