ISSN 0564-3783  

Main page
Information to authors
Editorial board
Mobile version

In Ukrainian

Export citations

Investigation of rs11536889 + 3725G/C polymorphism of the TLR4 gene in patients with autoimmune and chronic viral hepatitis C

Kucherenko A.M., rz L.V., Bvz .I., Bulavenko V.I., Antypkin Y.G., Berezenko V.S., Dyba M.B., Pampukha V.M., Gorodna O.V., Livshits L..


[Free Full Text (pdf)]Article Free Full Text (pdf)  

SUMMARY. Toll-like receptor 4 (encoded by TLR4 gene) has a variety of functions, including tissue homeostasis, regulation of cell death and survival via activation of signaling pathways which lead to interferon regulatory factor 3 (IRF-3) activation and type I interferon production. TLR4 may have a crucial role in pathogenesis of complex and infectious diseases. Functional polymorphism TLR4+3725G/C substitution (rs11536889) leads to faster transcript degradation and receptors number decrease. The study investigated TLR4 rs11536889 genotype and allele distribution in healthy volunteers from Ukraine (n = 155), autoimmune hepatitis (AH) children (n = 56) and chronic hepatitis C (CHC) adult patients with various fibrosis severity stages (n = 78). Genotyping was performed by allele-specific PCR. The obtained genotype frequencies in Ukrainian population were: GG genotype 0,813; GC 0,168; CC 0,019 and showed no significant deviation from the ones expected accord-ing to Hardy-Weinberg equilibrium. AH and CHC patients were divided according to METAVIR fibrosis score two groups with stage F1-F2, and with F3-F4. The frequency of rs11536889 C allele carriers were higher in the group of AH patients with F3-F4 (0,179) comparing to patients with F1-F2 (0,071). This data did not reach the threshold for significance but showed a trend toward association between C allele carriers and higher fibrosis degree. Moreover, the significantly (p <
< 0,05) higher frequency of C allele carriers was observed in CHC patients with higher fibrosis degree (0,400) compared to patients with lower degree (0,057). Severe liver damage risk in such individuals is 11-fold increased (OR = 11,11, 95 % CI: 2,7045,66). Thus, TLR4 rs11536889 C allele is associated with higher level of fibrotic liver damage in patients with chronic hepatitis.

Key words: Autoimmune hepatitis, Viral hepatitis C, Liver fibrosis, Single nucleotide polymorphism, Toll-like receptor TLR4

Tsitologiya i Genetika 2019, vol. 53, no. 4, pp. 41-49

E-mail: livshits

Kucherenko A.M., rz L.V., Bvz .I., Bulavenko V.I., Antypkin Y.G., Berezenko V.S., Dyba M.B., Pampukha V.M., Gorodna O.V., Livshits L.. Investigation of rs11536889 + 3725G/C polymorphism of the TLR4 gene in patients with autoimmune and chronic viral hepatitis C, Tsitol Genet., 2019, vol. 53, no. 4, pp. 41-49.

In "Cytology and Genetics":
A. M. Kucherenko, L. V. Moroz, T. I. Bevz, V. I. Bulavenko, Y. G. Antypkin, V. S. Berezenko, M. B. Dyba, V. M. Pampukha, O. V. Gorodna, L. A. Livshits Investigation of rs11536889 + 3725G/C Polymorphism of the TLR4 Gene in Patients with Autoimmune and Chronic Viral Hepatitis C, Cytol Genet., 2019, vol. 53, no. 4, pp. 300306
DOI: 10.3103/S0095452719040078


1. Huang, H., Shiffman, M.L., Friedman, S., Venkatesh, R., Bzowej, N., Abar, O.T., et al., A 7 gene signature identifies the risk of developing cirrhosis in patients with chronic hepatitis C, Hepatology, 2007, vol. 46, no. 2, pp. 297306.

2. Li Yonghong, Monica Chang, Olivia Abar, Veronica Garcia, Charles Rowland, Joseph Catanese, David Ross, Samuel Broder, Mitchell Shiffman, Ramsey Cheung, Teresa Wright, Scott L. Friedman, and John Sninsky, Multiple variants in Toll-like receptor 4 gene modulate risk of liver fibrosis in Caucasians with chronic hepatitis C infection, J. Hepatol., 2009, vol. 51, no. 4, pp. 750757.

3. Hishida, A., Matsuo, K., Goto, Y., Naito, M., Wakai, K., Tajima, K., and Hamajima, N., Combined effect of miR-146a rs2910164 G/C polymorphism and Toll-like receptor 4 +3725 G/C polymorphism on the risk of severe gastric atrophy in Japanese, Digest. Dis. Sci., 2011, vol. 56, no. 4, pp. 11311137.

4. Mollen, K.P., Anand, R.J., Tsung, A., Prince, J.M., Levy, R.M., and Billiar, T.R., Emerging paradigm: Toll-like receptor 4-sentinel for the detection of tissue damage, Shock, 2006, vol. 26, pp. 430437.

5. Ashham Mansur, Luisa von Gruben, Aron F. Popov, Maximilian Steinau, Ingo Bergmann, Daniel Ross, Michael Ghadimi, Tim Beissbarth, Martin Bauer, and José Hinz, The regulatory toll-like receptor 4 genetic polymorphism rs11536889 is associated with renal, coagulation and hepatic organ failure in sepsis patients, J. Translat. Med., 2014, vol. 12, pp. 177185.

6. Murillo G., Nagpal V., Tiwari N., Benya R.V., Mehta R.G. Actions of vitamin D are mediated by the TLR4 pathway in inflammation-induced colon cancer, J. Steroid. Biochem. Mol. Biol., 2010, vol. 121, no. 12, pp. 40310.

7. Penas-Steinhardt, A., Barcos, L.S., Belforte, F.S., de Sereday, M., Vilarico, J., Gonzalez, C.D., Martínez-Larrad, M.T., Tellechea, M.L., Serrano-Ríos, M., Poskus, E., Frechtel, G.D., and Coluccio Leskow, F., Functional characterization of TLR4 +3725 G/C polymorphism and association with protection against overweight, PLoS One, 2012, vol. 7, no. 12, pp. 18.

8. Tolstopyatova, M.A., Buslaeva, G.A., and Kozlov, I.G., The role of receptors of innate immunity in development of infectious disease and newborn babies, Pediatriya, 2009, vol. 87, no. 1, pp. 115120.

9. Poynard, T., Bedossa, P., and Opolon, P., Natural history of liver fibrosis progression in patients with chronic hepatitis C. The OBSVIRC, METAVIR, CLINIVIR, and DOSVIRC groups, Lancet, 1997, vol. 349, pp. 825832. PMID: .9121257

10. Maniatis, T., Fritsch, E.F., and Sambrook, J., Molecular Cloning: A Laboratory Manual, New York: Cold Spring Harbor Lab., 1982.

11. Hishida, A., Matsuo, K., and Goto, Y., Toll-like receptor 4 +3725 G/C polymorphism, Helicobacter pylori seropositivity, and the risk of gastric atrophy and gastric cancer in Japanese, Helicobacter, 2009, vol. 14, no. 1, pp. 4753.

12. Rousset, F., Genepop007: a complete re-implementation of the Genepop software for Windows and Linux, Mol. Ecol. Resour., 2008, vol. 8, no. 1, pp. 103106.

13. Clarke, G.M., Anderson, C.A., Pettersson, F.H., Cardon, L.R., Morris, A.P., and Zondervan, K.T., Basic statistical analysis in genetic case-control studies, Nat. Protoc., 2011, vol. 6, no. 2, pp. 121133.

14. Szumilas, M., Explaining odds ratios, J. Can. Acad. Child Adolesc. Psychiatry, 2010, vol. 19, no. 3, pp. 227229. PMID: .20842279

15. Sullivan, K., Dean, A., and Soe, M., OpenEpi: a web-based epidemiologic and statistical calculator for public health, Public. Heal. Rep., 2009, vol. 124, no. 3, pp. 471474.

16. Asselah, T., Bieche, I., Paradis, V., Bedossa, P., Vidaud, M., and Marcellin, P., Genetics, genomics, and proteomics: implications for the diagnosis and the treatment of chronic hepatitis C, Semin. Liver Dis., 2007, vol. 27, pp. 1327.

17. Novo, E., Marra, F., Zamara, E., Valfre di Bonzo, L., Monitillo, L., Cannito, S., Petrai, I., Mazzocca, A., Bonacchi, A., De Franco, R.S., Colombatto, S., Autelli, R., Pinzani, M., and Parola, M., Overexpression of Bcl-2 by activated human hepatic stellate cells: resistance to apoptosis as a mechanism of progressive hepatic fibrogenesis in humans, Gut, 2006, vol. 55, pp. 11741182.

18. Xu, L., Hui, A.Y., Albanis, E., Arthur, M.J., OByrne, S.M., Blaner, W.S., Mukherjee, P., Friedman, S.L., and Eng, F.J., Human hepatic stellate cell lines, LX-1 and LX-2: new tools for analysis of hepatic fibrosis, Gut, 2005, vol. 54, pp. 14251.

19. Guo, J. and Friedman, S., Hepatic fibrogenesis, Semin. Liver Dis., 2007, vol. 27, no. 4, pp. 413426.

20. Lorenz, E., Mira, J.P., Frees, K.L., and Schwartz, D.A., Relevance of mutations in the TLR4 receptor in patients with gram-negative septic shock, Arch. Int. Med., 2002, vol. 162, no. 9, pp. 10281032. PMID: 11996613

21. Agnese, D.M., Calvano, J.E., Hahm, S.J., Coyle, S.M., Corbett, S.A., Calvano, S.E., and Lowry, S.F., Human toll-like receptor 4 mutations but not CD14 polymorphisms are associated with an increased risk of gram-negative infections, J. Infect. Dis., 2002, vol. 186, no. 10, pp. 15221525.

22. Beutler, B., Inferences, questions and possibilities in Toll-like receptor signaling, Nature, 2004, vol. 430, pp. 257263.

23. Paik, Y.H., Schwabe, R.F., Bataller, R., Russo, M.P., Jobin, C., and Brenner, D.A., Toll-like receptor 4 mediates inflammatory signaling by bacterial lipopolysaccharide in human hepatic stellate cells, Hepatology, 2003, vol. 37, no. 5, pp. 10431055.

24. Su, G.L., Klein, R.D., Aminlari, A., Zhang, H.Y., Steinstraesser, L., Alarcon, W.H., Remick, D.G., and Wang, S.C., Kupffer cell activation by lipopolysaccharide in rats: role for lipopolysaccharide binding protein and Toll-like receptor 4, Hepatology, 2000, vol. 31, pp. 932936.

25. Seki, E., De Minicis, S., Osterreicher, C.H., Kluwe, J., Osawa, Y., Brenner, D.A., and Schwabe, R.F., TLR4 enhances TGF-beta signaling and hepatic fibrosis, Nat. Med., 2007, vol. 13, pp. 13241332.

26. Elsharkawy, A.M., Oakley, F., and Mann, D.A., The role and regulation of hepatic stellate cell apoptosis in reversal of liver fibrosis, Apoptosis, 2005, vol. 10, no. 5, pp. 927939.

27. Thacher, T.D. and Clarke, B.L., Vitamin D insufficiency, Mayo Clin. Proc., 2011, vol. 86, no. 1, pp. 5060.

28. Friedman, S.L., Hepatic stellate cells: protean, multifunctional, and enigmatic cells of the liver, Physiol. Rev., 2008, vol. 88, no. 1, pp. 125172.

29. Guo, J., Loke, J., Zheng, F., Hong, F., Yea, S., Fukata, M., Tarocchi, M., Abar, O.T., Huang, H., Sninsky, J.J., and Friedman, S.L., Functional linkage of cirrhosis-predictive single nucleotide polymorphisms of Toll-like receptor 4 to hepatic stellate cell responses, Hepatology, 2009, vol. 49, no. 3, pp. 960968.

30. Abreu M.T., Vora P., Faure E., Thomas L.S., Arnold E.T., Arditi M. Decreased expression of Toll-like receptor-4 and MD-2 correlates with intestinal epithelial cell protection against dysregulated proinflammatory gene expression in response to bacterial lipopolysaccharide, J. Immunol., 2001, vol. 167, no. 3, pp. 16091616.

31. Paula Piñero, Oriol Juanola, Esther Caparrós, Pedro Zapater, Paula Giménez, José M. González-Navajas, José Such, and Rubén Francés, Toll-like receptor polymorphisms compromise the inflammatory response against bacterial antigen translocation in cirrhosis, Nat. Sci. Rep., 2017, vol. 7, p. 46 425.

Copyright© ICBGE 2002-2022 Coded & Designed by Volodymyr Duplij Modified 01.07.22