The Role of Human Genetic Factors in the Natural Selection of Hepatitis C Virus’ Dominant Genotype in Ethnically Close Populations of Buryats and Khalkha-Mongols
The aim of the study was to assess the role of the innate immunity gene polymorphism in the population selection of hepatitis C virus (HCV) genotypes circulating in the ethnically close groups of Mongoloids: Buryats and Khalkha-Mongols.
Materials and Methods. Nucleotide polymorphisms of innate immunity genes were identified in 400 patients with chronic hepatitis C, including 200 people belonging to the ethnic group of Mongols living in Ulaanbaatar (Mongolia) and 200 to the ethnic group of Buryats living in Ulan-Ude (Republic of Buryatia). The control group (n=531) consisted of apparently healthy people comprising 220 Buryats and 311 Khalkha-Mongols. Genetic studies of twelve single-nucleotide polymorphisms of nine genes: IFNL1 (rs30461); IFNL3 (rs12979860 and rs8099917); IFNL4 (rs368234815); CD209 (rs4804803); TLR3 (rs3775291 and rs13126816); TLR7 (rs179008 and rs179009); IFITM (rs12252); MyD88 (rs6853); IFIH1 (rs1990760) have been performed in the mentioned selections of the sick and healthy individuals. When analyzing the genetic study results, frequencies of gene alleles and their combinations in the form of genotypes have been compared.
Results. The dominant prevalence of the HCV genotype 1 (98.0%) was found in the territory of Mongolia which appeared to be significantly higher (p<0.001) than its prevalence in the territory of Buryatia (66.0%). Among the genetic factors which can influence the formation of the circulating genotype structures in Buryat and Mongolian population, single-nucleotide polymorphisms in three genes (IFNL3, TLR3, and TLR7), the frequency of which differed significantly in the examined cohorts, have been detected. In the ethnical Buryat group, the search for the candidate genes in patients with chronic hepatitis C genotype 1 and non-1 (2 or 3, 2/3) has established that T allele of rs179008 TLR7 gene occurs 2 times more often in women with chronic hepatitis C infection caused by genotype 2/3 than by genotype 1 (p=0.04).
Conclusion. A low prevalence of HCV genotypes 2 and 3 among the population in the territory of Mongolia is likely to be caused by a rare frequency of the mutant T allele of TLR7 gene (rs179008) associated with the predisposition to HCV-2/3 infection, i.e. the situation that has been demonstrated in our work using the ethnical group of Buryats as an example.
- Lavanchy D. Evolving epidemiology of hepatitis C virus. Clin Microbiol Infect 2011; 17(2): 107–115, https://doi.org/10.1111/j.1469-0691.2010.03432.x
- Global hepatitis report 2017. Geneva: World Health Organization; 2017.
- Gower E., Estes C., Blach S., Razavi-Shearer K., Razavi H. Global epidemiology and genotype distribution of the hepatitis C virus infection. J Hepatol 2014; 61(1 Suppl): S45–S57, https://doi.org/10.1016/j.jhep.2014.07.027.
- Baatarkhuu O., Kim D.Y., Ahn S.H., Nymadawa P., Dahgwahdorj Y., Shagdarsuren M., Park J.Y., Choi J.W., Oyunbileg J., Oyunsuren T., Han K.H. Prevalence and genotype distribution of hepatitis C virus among apparently healthy individuals in Mongolia: a population-based nationwide study. Liver Int 2008; 28(10): 1389–1395, https://doi.org/10.1111/j.1478-3231.2008.01820.x.
- Malov S.I. Sravnitel’naya kliniko-epidemiologicheskaya kharakteristika virusnogo gepatita C na sopredel’nykh territoriyakh Rossii i Mongolii. Avtoref. dis. … kand. med. nauk [Comparative clinical and epidemiological characteristics of viral hepatitis C on the cross-border regions of Russia and Mongolia. PhD Thesis]. Moscow; 2017.
- Nikitina G.Yu., Semenenko T.A., Gotvyanskaya T.P., Hahaeva I.B., Konopleva M.V., Nikolaeva O.G., Yarosh L.V., Kozhevnikova L.K., Suslov A.P. The prevalence of parenteral hepatitis markers among the medical personnel in the Russian Federation regions with different intensity of epidemic process. Klinicheskaya mikrobiologiya i antimikrobnaya khimioterapiya 2017; 19(2): 161–167.
- Ryan E.J., Dring M., Ryan C.M., McNulty C., Stevenson N.J., Lawless M.W., Crowe J., Nolan N., Hegarty J.E., O’Farrelly C. Variant in CD209 promoter is associated with severity of liver disease in chronic hepatitis C virus infection. Hum Immunol 2010; 71(8): 829–832, https://doi.org/10.1016/j.humimm.2010.05.007.
- Jiménez-Sousa M.A., Rallón N., Berenguer J., Pineda-Tenor D., López J.C., Soriano V., Guzmán-Fulgencio M., Cosín J., Retana D., García-Álvarez M., Miralles P., Benito J.M., Resino S. TLR3 polymorphisms are associated with virologic response to hepatitis C virus (HCV) treatment in HIV/HCV coinfected patients. J Clin Virol 2015; 65: 62–67, https://doi.org/10.1016/j.jcv.2015.02.004.
- Barkhash A.V., Perelygin A.A., Babenko V.N., Brinton M.A., Voevoda M.I. Single nucleotide polymorphism in the promoter region of the CD209 gene is associated with human predisposition to severe forms of tick-borne encephalitis. Antiviral Res 2012; 93(1): 64–68, https://doi.org/10.1016/j.antiviral.2011.10.017.
- Kruchkin Yu.N. Sovremennaya Mongoliya. Entsiklopedicheskii spravochnik [Modern Mongolia. Encyclopedic reference book]. Ulan-Bator; 2011; 1154 p.
- Simbirtsev A.S. Cytokines in the pathogenesis of infectious and noninfectious human diseases. Meditsinskiy akademicheskiy zhurnal 2013; 13(3): 18–41.
- Obaid A., Ahmad J., Naz A., Awan F.M., Paracha R.Z., Tareen S.H., Anjum S., Raza A., Baumbach J., Ali A. Modeling and analysis of innate immune responses induced by the host cells against hepatitis C virus infection. Integr Biol (Camb) 2015; 7(5): 544–559, https://doi.org/10.1039/c4ib00285g.
- Akaike H. A new look at the statistical model identification. IEEE Transactions on Automatic Control 1974; 19: 716–723, https://doi.org/10.1109/tac.1974.1100705.
- Pevnitsky L.A. Statistical assessment of associations between HLA antigens and diseases. Vestnik AMN SSSR 1988; 7: 48–51.
- Wietzke-Braun P., Maouzi A.B., Mänhardt L.B., Bickeböller H., Ramadori G., Mihm S. Interferon regulatory factor-1 promoter polymorphism and the outcome of hepatitis C virus infection. Eur J Gastroenterol Hepatol 2006; 18(9): 991–997, https://doi.org/10.1097/01.meg.0000224478.89545.76.
- Askar E., Bregadze R., Mertens J., Schweyer S., Rosenberger A., Ramadori G., Mihm S. TLR3 gene polymorphisms and liver disease manifestations in chronic hepatitis C. J Med Virol 2009; 81(7): 1204–1211, https://doi.org/10.1002/jmv.21491.
- Tanaka Y., Nishida N., Sugiyama M., Kurosaki M., Matsuura K., Sakamoto N., Nakagawa M., Korenaga M., Hino K., Hige S., Ito Y., Mita E., Tanaka E., Mochida S., Murawaki Y., Honda M., Sakai A., Hiasa Y., Nishiguchi S., Koike A., Sakaida I., Imamura M., Ito K., Yano K., Masaki N., Sugauchi F., Izumi N., Tokunaga K., Mizokami M. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat Genet 2009; 41(10): 1105–1109, https://doi.org/10.1038/ng.449.
- Qian F., Bolen C.R., Jing C., Wang X., Zheng W., Zhao H., Fikrig E., Bruce R.D., Kleinstein S.H., Montgomery R.R. Impaired toll-like receptor 3-mediated immune responses from macrophages of patients chronically infected with hepatitis C virus. Clin Vaccine Immunol 2013; 20(2): 146–155, https://doi.org/10.1128/cvi.00530-12.
- Svensson A., Tunbäck P., Nordström I., Padyukov L., Eriksson K. Polymorphisms in toll-like receptor 3 confer natural resistance to human herpes simplex virus type 2 infection. J Gen Virol 2012; 93(Pt 8): 1717–1724, https://doi.org/10.1099/vir.0.042572-0.
- Fakhir F.Z., Lkhider M., Badre W., Alaoui R., Meurs E.F., Pineau P., Ezzikouri S., Benjelloun S. Genetic variations in toll-like receptors 7 and 8 modulate natural hepatitis C outcomes and liver disease progression. Liver Int 2018; 38(3): 432–442, https://doi.org/10.1111/liv.13533.
- Askar E., Ramadori G., Mihm S. Toll-like receptor 7 rs179008/Gln11Leu gene variants in chronic hepatitis C virus infection. J Med Virol 2010; 82(11): 1859–1868, https://doi.org/10.1002/jmv.21893.
- Schott E., Witt H., Neumann K., Bergk A., Halangk J., Weich V., Müller T., Puhl G., Wiedenmann B., Berg T. Association of TLR7 single nucleotide polymorphisms with chronic HCV-infection and response to interferon-a-based therapy. J Viral Hepat 2008; 15(1): 71–78, https://doi.org/10.1111/j.1365-2893.2007.00898.x.