Цель работы-провести комплексную оценку иммуногенетических и биохимических показателей у больных ХГВ, проживающих в Одесском регионе. Материал и методы. Обследован 41 больной хроническим гепатитом В. Определены традиционные биохимические и иммунологические показатели, содержание цитокинов ИЛ-4, ИЛ-10, TNFα и полиморфизм генов цитокинов ИЛ-4, ИЛ-10, TNFα. Результаты. Для оценки взаимосвязи непараметрических и параметрических показателей (изменений иммунологического статуса, биохимических показателей и цитокинового профиля) больные были разделены на группы в соответствии с выявленными полиморфизмами генов цитокинов. С применением коэффициента ранговой корреляции Спирмена установлены определенные связи. У пациентов с гомозиготным полиморфизмом СС ИЛ-4 отмечались более выраженные изменения цитокинового профиля, иммунологического статуса и более высокий уровень активности АлАт и АсАт. Выводы. Выявленная взаимосвязь уровня АлАт и Асат, показателей иммунологического статуса и цитокинового профиля с определенными генотипами TNFα и ИЛ-4 позволяет предположить генетическую предрасположенность определенных больных ХГВ к более тяжелому течению. Полученная информация может быть применена как один из дополнительных критериев активности воспалительных изменений печеночной ткани.
According to recent WHO estimates, chronic HBV infection is one of the leading causes of death and disability in patients with infectious diseases. From 780 thousand to 1 million deaths are annually recorded in the world as a result of cirrhosis of the liver and hepatocellular carcinoma. Pathogenetic features of the course and outcomes of chronic hepatitis B are determined by the immunological, genetic factors of the host, as well as the molecular biological structure of the virus. The aim of the pilot study was to study the polymorphic loci of the cytokine genes SMAD 7 (rs4939827), TNFα (rs1800620), IL-10 (rs1800896), IL-4 (rs2243250) and the degree of structural changes in the liver based on the non-invasive Fibrotest technique in patients with chronic hepatitis B as part of a search for possible predictors of predisposition to the rapid progression of liver fi brosis. Material and methods. The pilot study included 41 patients with chronic hepatitis B. Assessment of morphological changes (stage of fi brosis) was carried out by the method of non-invasive diagnosis of Fibrotest, which is an alternative to puncture biopsy of the liver. Results. It has been suggested that homozygous SS alleles IL-4 (rs2243250), GG TNFα (rs1800620), SS SMAD family member 7 (rs4939827) have a protective eff ect on the course of chronic hepatitis B, as these variants of allelic polymorphism of cytokine genes were found mainly in patients with CHB with a degree of fi brosis F0-F1. The heterozygous genotypes CT IL-4 (rs2243250) and GA TNFα (rs1800620), the mutant homozygous TT genotype SMAD family member 7 (rs4939827) have a profi brotic eff ect on the course of chronic hepatitis B, as they are found mainly in patients with chronic hepatitis B with degree of fi brosis F3. Discussion. The established relationship between the liver fi brosis stage according to the METAVIR scale and the polymorphism of the cytokine genes SMAD 7 (rs4939827), TNFα (rs1800620) and IL-4 (rs2243250) made it possible to create a prognostic scale for assessing the individual risk of rapid progression of liver fi brosis. The proposed scale, due to a comprehensive assessment of the polymorphism of cytokine gene alleles and the stage of liver fi brosis using the METAVIR scale, makes it possible to carry out an individual assessment of the risk of progression of chronic hepatitis and, possibly, draw up a personalized treatment plan for the patient. Coding of the studied polymorphisms and subsequent counting can be automated, which does not require signifi cant fi nancial investments.
The data on the polymorphism of cytokine genes associated with individual reactivity on the effects of hepatitis C virus, predict the rate of progression of liver fibrosis. The purpose of this work is study the association of the polymorphic marker G308A of the TNFα gene with its quantitative content and degree of liver fibrosis in patients with chronic hepatitis C. A total of 100 patients with CSF were examined. The polymorphism of G308A gene’s TNFα was studied by amplification of the corresponding genome zones by PCR. The assessment of the degree of fibrosis was performed using the non-invasive Fibrotest method. The study of the quantity of TNFα cytokine in serum of patients was performed by ELISA. The distribution of genotypes on the investigated polymorphic loci was verified using Pearson's χ2 criterion. The frequencies of alleles and genotypes in the groups were compared using Pearson's χ2 criterion with Yates correction for continuity with the number of degrees of freedom 1. In order to detect the correlation dependencies between the individual parameters, the Spearman correlation coefficient was applied. It was found that a smaller degree of fibrosis was observed in carriers of the GG TNFα genotype, and a greater degree of fibrosis in the carriers of the genotype AA TNFα (moderate feedback between the degree of fibrosis and the genotypes of TNFα). The higher content of TNFα is noted in the carriers of the AA genotype TNFα, the lower content of TNFα - in the carriers of the GG TNFα genotype (moderate feedback between the TNFα genotypes and the TNFα content). It has been established that a higher TNFα content is observed in patients with F1-F0 fibrosis, a lower TNFα content in patients with F2-F3 fibrosis (a strong correlation between the degree of fibrosis and the amount of TNFα cytokine). It is assumed that the production of the cytokine is determined at the genetic level, and the severity of changes in the cytokine profile in chronic hepatitis C affects the course of the pathological process. An increase in the TNFα content in chronic hepatitis C may be a marker for significant morphological changes in the hepatic tissue and high activity of the inflammatory process.
Vestnik VGMU. 2016;15(3):47-52. Резюме.Цель -провести сравнительный анализ частоты встречаемости полиморфизмов генов IL-4(C589T), IL-10(G1082A), TNFα (G308A) у пациентов с хроническим гепатитом В (ХГВ) и с хроническим гепатитом С (ХГС), проживающих в Одесском регионе, для повышения качества диагностики на основе полученных генетических критериев. Материал и методы. Полиморфизм генов цитокинов изучался при помощи амплификации соответствую-щих участков генома методом ПЦР. Структура использованных праймеров и параметры температурных циклов использованы из международной геномной базы данных. Результаты. В этнически однородных группах жителей Одесского региона между пациентами с хрони-ческим гепатитом В и с хроническим гепатитом С выявлены различия по частотам аллелей гена TNFα (G308A) (р<0,05). При сравнительном анализе аллельного полиморфизма IL-4(C589T) и IL-10(G1082A) между группами пациентов с ХГС и ХГВ не обнаружено статистически значимого различия. Заключение. Существенные различия в полиморфизме генов TNFα (G308A) у пациентов с ХГС и ХГВ ука-зывают на возможность индивидуализации генетического профиля при различных гепатитах. Отсутствие существенной разницы частоты генотипов IL-4(C589T) и IL-10(G1082A) может служить подтверждением важной роли этих цитокинов в иммунологическом сегменте генетического профиля пациентов. Ключевые слова: хронический гепатит В, хронический гепатит С, полиморфизм генов цитокинов. Abstract.Objectives. To conduct a comparative analysis of the frequency of polymorphisms of IL-4 (C589T), IL-10 (G1082A), TNFα (G308A) in patients with chronic hepatitis B (CHB) and chronic hepatitis C (CHC), residing in Odessa region for the improvement of the diagnosis quality on the basis of the obtained genetic criteria. Material and methods. Cytokine gene polymorphism was studied using amplification of the corresponding regions of the genome by PCR method. The structure of the primers used and the parameters of temperature cycles were employed from the international genomic data base. Results. The differences in allele frequencies of TNFα gene (G308A) (p<0,05) were revealed in ethnically homogeneous groups of the inhabitants of Odessa region among patients with chronic hepatitis B and chronic hepatitis C. The comparative analysis of allelic polymorphism of IL-4 (C589T) and IL-10 (G1082A) in patients with CHC and CHB didn't show any statistically significant difference between them. Conclusions. Significant differences in gene polymorphism of TNFα (G308A) in patients with CHC and CHB indicate the possibility of genetic profile individualization in different hepatites. Thus, the absence of significant difference in the frequency of genotypes of IL-4 (C589T) and IL-10 (G1082A) can serve as a confirmation of the important role of these cytokines in the immunological genetic profile segment of patients.
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