Epidemiology and Infectious DiseasesEpidemiology and Infectious DiseasesЭпидемиология и инфекционные болезни3034-20073034-2015Eco-Vector4084310.17816/EID40843ArticlesСтатьиResearch Articleil 28B polymorphisms and the prognosis for the efficacy of antiviral therapy in viral hepatitis C patients in UzbekistanПолиморфизм гена il 28B и прогноз эффективности противовирусной терапии при вирусном гепатите с в УзбекистанеSeklerD. EСеклерД. Э

канд. мед. наук, ст. науч. сотрудник, руководитель группы в проекте «Определение резистентности к препаратам АРВТ у ВИЧ-инфицированных»

dildora@gmail.comKhudayberganovaD. MХудайбергановаД. М

стажер-исследователь

mail2dinara@gmail.comLatypovR. RЛатыповР. Р

зам. директора по научно-исследовательской работе

renatlatip@gmail.comUsmanovaG. ZУсмановаГ. З

зав. отд-нием гепатологии

RakhmanovM. IРахмановМ. И

канд. мед. наук, зам. гл. врача клиники

MusabaevE. IМусабаевЭ. И

доктор мед. наук, проф., директор НИИ вирусологии

drmusabaev@rambler.ruScientific Research Institute of VirologyНИИ вирусологии, МЗ РУз15122014196VOL 19, NO6 (2014)ТОМ 19, №6 (2014)374223072020Copyright ©; 2014, Eco-vectorCopyright ©; 2014, ООО "Эко-вектор"2014Eco-vectorООО "Эко-вектор"https://rjeid.com/1560-9529/article/view/40843

Introduction: By means of the Association for the Study of complete genome there was identified the prognostic value of polymorphisms associated with single-nucleotide substitutions (SNP) in the human genome and located in the region of the gene IL28B/IFN-L3. Hereafter also there were identified SNP in the gene IFN-L4 and there was found a correlation between the population and the spontaneous elimination of HCV infection. Methods: In the studies there was used the materialfrom 135 HCV-infected persons residing on the territory of Uzbekistan. DNA was isolated from peripheral blood mononuclear cells (PBMC), then SNP genotyping of the IFN-L3 gene region (rs8099917, rs12979860) was performed by means of three methods: Invader Plus Assay, TaqMan Assay and direct sequencing. The plot of the IFN-L4 gene (ss469415590) was sequenced. Results: Out of the 135 studied patients, who received antiviral treatment according to the standard scheme Peg-IFN-a in combination with RBVfor 24 and 48 weeks, 87,4% were belonged to the Central Asian (CA) ethnic group and 12.6% - Eastern European (EE). Among the examined cases, there no virological response to antiviral therapy was observed in 21.2% of patients from CA group and 35.3% of EE patients (p <0.32). High association of SNP rs12979860 was observed in the testing of all samples with sustained antiviral response to the therapy (OR, 5.2; 95% CI, 1.9 - 14.6; p <0.004), but the SNP rs8099917 showed a high prognostic significance only in the CA group (OR, 6.9; 95 % CI, 2.6 - 18.0; p <0.002). Allele frequencies IFNL4 SNP rs469415590 were met similarly to SNP rs12979860 in the all studied samples. Conclusions: For the prediction of the outcome ofantiviral therapy in viral hepatitis C among populations of Central Asia, SNP regions and genes IFNL3IFNL4 can be used as markers of genetic factors.

Введение. Ассоциацией по исследованиям полного генома было выявлено прогностическое значение полиморфизма, связанного с однонуклеотидными заменами (SNP) в геноме человека и расположенных в участке гена IL28B/IFNL3. В дальнейшем также были выявлены SNP в области гена IFNL4 и обнаружена корреляция между популяцией и спонтанным элиминированием ВГС-инфекции. Методы. В исследованиях использовался материал от 135 ВГС-инфицированных лиц, проживающих на территории Узбекистана. ДНК выделяли из мононуклеарных клеток периферической крови (PBMC), далее генотипирование SNP участка гена IFNL3 (rs8099917, rs12979860) проводили тремя методами: Invader Plus Assay, TaqMan Assay и прямым секвенированием. Участок гена IFNL4 (ss469415590) секвенировали. Результаты. Из 135 обследованных пациентов, получавших 24 и 48 нед противовирусное лечение по стандартной схеме Peg-IFN-a в сочетании с RBV, 87,4% относились к центрально-азиатской (ЦЛ) этнической группе и 12,6% - к восточно-европейской (ВЕ). Среди обследованных не наблюдался вирусологический ответ на противовирусную терапию у 21,2% ЦА-группе и 35,3% ВЕ (р < 0,32). Высокая ассоциация SNP rs12979860 наблюдалась при тестировании всех образцов с устойчивым противовирусным ответом на терапию (OR 5,2; 95% CI 1,9-14.6; p < 0,004), однако SNP rs8099917 показало высокую прогностическую значимость только среди ЦА-группы (OR 6,9; 95% CI 2,6-18,0; p < 0,002). Частота аллелей IFNL4 SNP rs469415590 встречалась идентично SNP rs12979860 во всех исследованных образцах. Заключение. Для прогноза исхода противовирусной терапии при вирусном гепатите С среди популяций ЦА, в качестве маркеров генетических факторов могут быть использованы SNP областей генов IFNL3 и IFNL4.

IL28B polymorphismhepatitis Cantiviral therapyполиморфизм IL28Bгепатит Спротивовирусная терапияHanafiah K.M., Groeger J., Flaxman A.D., Wiersma S.T. Global epidemiology of hepatitis C virus infection: New estimates of age-specific antibody to hepatitis C virus seroprevalence. Hepatology. 2013; 57: 1333-42.Bernhardt S., Rutter K., Stattermayer A. 1 F., Ferenci P. Revisiting the predictors of a sustained virologic response in the era of direct-acting antiviral therapy for hepatitis C virus. Clin. Infect. Dis. 2013; 56: 118-22.Ghany M.G., Strader D.B., Thomas D.L., Seeff L.B. Diagnosis, management,and treatment of hepatitis C: an update. Hepatology. 2009; 49: 1335-74.Tanaka Y., Nishida N., Sugiyama M., Tokunaga K., Mizokami M. lambda- interferons and the single nucleotide polymorphisms: A milestone to tailor-made therapy for chronic hepatitis C. Hepatol. Res. 2010; 40: 449-60.Hayes C.N., Imamura M., Aikata H., Chayama K. Genetics of IL28B and HCV-response to infection and treatment. Nat. Rev. Gastroenterol. Hepatol 2012; 9: 406-17.Hayes C.N., Kobayashi M., Akuta N., Suzuki F., Kumada H. et al. HCV substitutions and IL28B polymorphisms on outcome of peg-interferon plus ribavirin combination therapy. Gut. 2011; 60: 261-7.Ge D., Fellay J., Thompson A.J., Simon J.S., Shianna K.V. et al. Genetic variation in IL28B predicts hepatitis C treatmentinduced viral clearance. Nature. 2009; 461: 399-401.Suppiah V., Moldovan M., Ahlenstiel G., Berg T., Weltman M. et al. IL28B is associated with response to chronic hepatitis C interferon-alpha and ribavirin therapy. Nat. Genet. 2009; 41: 1100-4.Tanaka Y., Nishida N., Sugiyama M., Kurosaki M., Matsuura K. et al. Genome-wide association of IL28B with response to pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C. Nat. Genet. 2009; 41: 1105-9.Rauch A., Kutalik Z., Descombes P.1., Cai T., Di Iulio J. et al. Genetic variation in IL28B is associated with chronic hepatitis C and treatment failure: a genome wide association study. Gastroenterology. 2010; 138: 1337-8.Prokunina-Olsson L., Muchmore B., Tang W., Pfeiffer R.M., Park H. et al. A variant upstream of IFNL3 (IL28B) creating a new interferon gene IFNL4 is associated with impaired clearance of hepatitis C virus. Nat. Genet. 2013; 45: 164-71.Clark P.J., Thompson A.J., McHutchison J.G. IL28B genomicbased treatment paradigms for patients with chronic hepatitis C infection: the future of personalized HCV therapies. Am. J. Gastroenterol. 2011; 106: 38-45.Clark P.J., Thompson A.J. Host genomics and HCV treatment response. J. Gastroenterol. Hepatol. 2012; 27: 212-22.Stattermayer A.F., Strassl R., Maieron A., Rutter K., Stauber R. et al. Polymorphisms of interferon-74 and IL28B - effects on treatment response to interferon/ribavirin in patients with chronic hepatitis C. Aliment. Pharmacol. Ther. 2014; 39: 104-11.Covolo L., Bibert S., Donato F., Bochud P.-Y., Lagging M. et al. The novel ss469415590 variant predicts virological response to therapy in patients with chronic hepatitis C virus type 1 infection. Aliment. Pharmacol. Ther. 2013; 1-9.Franco S., Aparicio E., Parera M., Clotet B., Tural C. et al. IFNL4 ss469415590 variant is a better predictor than ILF3 (IL28B) rs12979860 of pegylated interferon-alpha/ribavirin therapy failure in hepatitis C virus/HIV-1 coinfected patients. AIDS. 2013; 131-6.Kramer B., Nischalke H.D., Boesecke 1 C., Ingiliz P., Voigt E. et al. Variation in IFNL4 genotype and response to interferon-based therapy of hepatitis C in HIV positive patients with acute and chronic hepatitis C. AIDS. 2013; 6: 27-9.Bibert S., Roger T., Calandra T., Bochud M., Cerny A. et al. IL28B expression depends on a novel TT/-G polymorphism which improves HCV clearance prediction. J. Exp. Med. 2013; 210: 1109-16.Nozawa Y., Umemura T., Katsuyama Y., Shibata S., Kimura T. et al. Genetic polymorphism in IFNL4 and response to pegylated interferon-a and ribavirin in Japanese chronic hepatitis C patients. Tissue. Antigens. 2014; 83: 45-8.Fujino H., Imamura M., Nagaoki Y., Kawakami Y., Abe H. et al Predictive value of the IFNL4 polymorphism on outcome of telaprevir, peginterferon, and ribavirin therapy for older patients with genotype 1b chronic hepatitis C. J. Gastroenterol. 2013.Ruzibakiev R., Kato H., Ueda R., Yuldasheva N., Hegay T. et al. Risk factors and seroprevalence of hepatitis B virus, hepatitis C virus, and human immunodeficiency virus infection in uzbekistan. Intervirology. 2001; 44: 327-32.Kurbanov F., Tanaka Y., Avazova D., Khan A., Sugauchi F. et al. Detection of hepatitis C virus natural recombinant RF1_2k/1b strain among intravenous drug users in uzbekistan. Hepatol. Res. 2008; 38: 457-64.Kurbanov F., Tanaka Y., Sugauchi F., Kato H., Ruzibakiev R. et al. Hepatitis C virus molecular epidemiology in Uzbekistan. J. Med Virol. 2003; 69: 367-75.Ito K., Higami K., Masaki N., Sugiyama M., Mukaide M. et al. The rs8099917 polymorphism, when determined by a suitable genotyping method, is a better predictor for response to pegylated a 1 lpha interferon/ribavirin therapy in Japanese patients than other single nucleotide polymorphisms associated with interleukin-28B. J. Clin. Microbiol. 2011; 49: 1853-60.Lindh M., Lagging M., Norkrans G., Hellstrand K. A model explaining the correlations between IL28B-related genotypes, hepatitis C virus genotypes, and viral RNA levels. Gastroenterology. 2010; 139: 1794-6.Fischer J., Bohm S., Scholz M., Muller T., Witt H. et al. Combined effects of different IL28B gene variants on the outcome of dual combination therapy in chronic HCV type 1 infection. Hepatology. 2012; 55: 1700-10.