Взаимосвязь полиморфных локусов, расположенных в промоторных областях генов VEGF (rs699947 и rs2010963), ICAM1 (rs281437) и ET-1 (rs1800541), с уровнем соответствующих белковых продуктов в сыворотке крови и риском развития алкогольного цирроза печени

Background: Uncontrolled use of alcohol can lead to the development of cirrhosis of the liver, which is manifested by fibrosis with the formation of regenerative nodes, an increase in pressure in the portal vein system and impaired liver function. Hepatic endothelium dysfunction during the formation of portal hypertension is accompanied by an increase in the level of protein molecules involved in the functioning of the endothelium: vascular endothelial growth factor A (VEGF-A), a soluble form of the intercellular adhesion molecule (s-ICAM-1) and endothelin-1 (ET -one). It is assumed that elevated levels of VEGF-A, s-ICAM-1 and ET-1 in alcoholic liver cirrhosis (AHC) may be interconnected with the structure of polymorphic loci, the promoter regions of the respective genes, which in turn may be a genetic risk factor for developing cirrhosis.Aims: Investigate the relationship of carriage of variant forms of polymorphic loci located in the promoter regions of VEGF-A, ICAM-1 and ET-1 with the level of the corresponding proteins in the blood serum and the risk of AHC.Materials and methods: The main group consisted of patients with pathological dependence on alcohol, aggravated by cirrhosis of the liver (AHC, n=60). The control group consisted of persons suffering from alcohol abuse, without liver pathology (AA, n=24). The observation period was the period of hospitalization. The serum levels of VEGF-A, s-ICAM-1 and ET-1 were evaluated by enzyme immunoassay. The distribution of variant forms of polymorphic loci located in the promoter regions of the VEGF-A genes (rs699947 and rs2010963), ICAM1 (rs281437) and ET-1 (rs1800541) in the studied sample was performed by real-time PCR.Results: The development of alcoholic cirrhosis was accompanied by a significant increase in the concentration of VEGF-A, s-ICAM-1 and ET-1 in serum. At the same time, direct correlations between the concentrations of VEGF-A, s-ICAM-1 and ET-1 in serum and the diameter of the portal vein in persons with liver cirrhosis were revealed. Patients with AHC are often carriers of the G allele of rs1800541 locus, located in the promoter of the ET-1 gene, compared with individuals suffering from control without liver pathology, which is associated with an increased risk of developing cirrhosis in alcohol dependence. The carriage of the C allele rs699947, as well as the C allele rs2010963 located in the promoter of the VEGF gene was associated with an increased level of VEGF-A in the AHC compared to carriers of this allele in the AA group. In addition, in the group of patients with AHC, carriers of allele C, homozygous CC genotype and heterozygous GC genotype of rs2010963 locus compared with carriers of G allele or homozygous GG genotype, respectively, were characterized by elevated serum VEGF-A levels.Conclusion: Carrier allele G of the rs1800541 locus (ET-1) is a risk factor for liver cirrhosis with alcohol abuse. The carriage of the C allele rs699947, as well as the C allele rs2010963 located in the promoter of the VEGF gene, can determine the elevated serum VEGF-A level in the AHC.Обоснование. Неконтролируемое употребление алкоголя может обусловливать развитие цирроза печени, который проявляется фиброзом с образованием узлов-регенератов, повышением давления в системе воротной вены и нарушением функции печени. Дисфункция печеночного эндотелия при формировании портальной гипертензии сопровождается повышением уровня молекул белковой природы, участвующих в функционировании эндотелия, ― васкулоэндотелиального фактора роста А (VEGF-A), растворимой формы молекулы межклеточной адгезии (s-ICAM-1) и эндотелина-1 (ET-1). Предполагается, что повышенный уровень VEGF-A, s-ICAM-1 и ET-1 при алкогольном циррозе печени (АЦП) может быть взаимосвязан со строением полиморфных локусов промоторных областей соответствующих генов, что в свою очередь может являться генетическим фактором риска развития цирроза печени.Цель ― исследовать взаимосвязь носительства вариантных форм полиморфных локусов, расположенных в промоторных областях VEGF-A, ICAM-1 и ET-1, с уровнем соответствующих белков в сыворотке крови и риском развития АЦП.Методы. Основную группу составили пациенты с патологической зависимостью от алкоголя, отягощенной циррозом печени (АЦП, n=60). Группу контроля составили лица, страдающие алкогольной зависимостью, без патологии печени (АЗ, n=24). Период наблюдения равнялся периоду госпитализации. Содержание VEGF-A, s-ICAM-1 и ET-1 в сыворотке крови оценивали посредством иммуноферментного анализа. Распределение вариантных форм полиморфных локусов, расположенных в промоторных областях генов VEGF-A (rs699947 и rs2010963), ICAM1 (rs281437) и ET-1 (rs1800541), в исследуемой выборке проводили с помощью полимеразной цепной реакции в режиме реального времени.Результаты. Развитие алкогольного цирроза печени сопровождалось значительным повышением концентрации VEGF-A, s-ICAM-1 и ET-1 в сыворотке крови. При этом были выявлены прямые корреляционные отношения между значениями концентрации VEGF-A, s-ICAM-1 и ET-1 в сыворотке крови и диаметром портальной вены у лиц с циррозом печени. Пациенты с АЦП чаще являются носителями аллеля G локуса rs1800541, расположенного в промоторе гена ET-1, по сравнению с лицами, страдающими АЗ без патологии печени, что сопряжено с повышенным риском развития цирроза при алкогольной зависимости. Носительство аллеля С локуса rs699947, а также аллеля С локуса rs2010963, расположенных в промоторе гена VEGF, было связано с повышенным уровнем VEGF-A при АЦП по сравнению носителями данного аллеля в группе АЗ. Кроме того, в группе пациентов с АЦП носители аллеля С, гомозиготного генотипа СС и гетерозиготного генотипа GC локуса rs2010963 по сравнению с носителями аллеля G или гомозиготного генотипа GG соответственно характеризовались повышенным уровнем VEGF-A в сыворотке крови.Заключение. Носительство аллеля G локуса rs1800541 (ET-1) является фактором риска развития цирроза печени при злоупотреблении алкоголем. Носительство аллеля С локуса rs699947, а также аллеля С локуса rs2010963, расположенных в промоторе гена VEGF, может определять повышенный уровень VEGF-А в сыворотке крови при АЦП

Single nucleo tide polymorphisms in cytokine genes and their role in the pathogenesis of cardiac , vascular and pulmonary diseases

The purpose of the literature review is to analyze the current data on the influence of cytokine gene polymorphisms on the occurrence, course, manifestations and outcomes of the most common cardiac, vascular and pulmonary diseases, in the pathogenesis of which inflammation plays a significant role. The range of cytokines under consideration includes classes that potentiate the inflammatory process (pro-inflammatory cytokines), which include TNF-α, IL-1, IL-6, IL-12, IL-13, IL-17 and IL-33, and its inhibitors (anti-inflammatory), such as IL-10, IL-4, TGF-β. The role of cytokine polymorphismsin the development of dilated cardiomyopathy, ischemic heart disease, heart failure, stroke, bronchial asthma and chronic obstructive pulmonary disease is discussed. The data obtained so far indicate that the content and severity of the effect of cytokine gene polymorphisms on the pathological process depends on the polymorphic locus location, its effect on gene expression, the combination of polymorphism alleles and the ethnic characteristics of patients. © 2021 Stavropol State Medical University. All rights reserved

Значение иммуновоспалительных и генетических факторов в развитии алкогольного фиброза печени

E role of immune-inflammatory and genet- ic factors in the development of liver fibrosis in patients with alcohol liver disease (ALD).Material and methods. Forty-six patients with ALD (35 males, mean age 50.2±11.5 years) were enrolled in our study and were distributed into two groups depending on the stage of liver fibrosis, that was determined by transient elastometry (F0+1, n=10; F3+4, n=36). We measured serum interleukin(IL)-6, IL-8, tumor necrosis factor (TNF)-α, VEGF-A, sICAM-1,ET-1 levels and gene polymorphism of TNF-α (rs1800629), IL-6 (rs1800795), VEGF-A (rs699947), ICAM1 (rs281437), ET-1 (rs1800541), IL-8 (rs4073).Results. Serum IL-6, IL-8, TNF-α, VEGF-A, sICAM-1 levelsin patients with ALD were higher than the reference values. Serum IL-6, IL-8, sICAM-1 and ET-1 levels depended on the degree of alcoholic liver fibrosis. Degree of liver fibrosis sig- nificantly correlated with IL-6 (r = 0.60), IL-8 (r = 0.77), sICAM-1 (r = 0.58) and ET-1 (r = 0.56). There were no signifi-cant differences in the TNF-α and VEGF-A levels between thetwo groups. Different alleles and genotypes of the studied genes occurred with similar frequency in the two groups. In both groups, VEGF-A level in patients with genotypes CA of the rs699947 C2578A gene was higher than in patients with genotype AA (p = 0.04 and p = 0.01). In advanced fibrosis, genotype TT of the rs281437 -451CT gene was associated with a higher sICAM-1 compared with genotype CC (p=0.05)Conclusion. Patients with ALD presented with increased levels of pro-inflammatory cytokines (IL-6, IL-8) and molecules of endothelial dysfunction (EТ1, sICAM-1). Genotype CA ofЦель. Изучить иммуновоспалительные и гене-тические факторы, участвующие в развитиифиброза печени у пациентов, злоупотребляю-щих алкоголем.Материал и методы. В исследование быливключены 46 пациентов (средний возраст50,2±11,5 лет, 35 мужчин) с алкогольнойболезнью печени (АБП), распределенных нагруппы в зависимости от степени фиброзапечени, которую определяли методом непря-мой эластометрии: 1-я - F0+1 (n=20), 2-я - F3+4 (n=36). У всех больных измеряли кон-центрации интерлейкина (ИЛ)-6, ИЛ-8, факторанекроза опухоли (ФНО)-α, VEGF-A, sICAM-1,эндотелина (ЭТ)-1 и полиморфизм геновФНО-α (rs1800629), ИЛ-6 (rs1800795),VEGF-A (rs699947), ICAM-1 (rs281437),ЭТ-1 (rs1800541), ИЛ-8 (rs4073).Результаты. У пациентов с АБП концентра-ции ИЛ-6, ИЛ-8, ФНО-α, VEGF-A, sICAM-1были выше референтных значений. УровниИЛ-6, ИЛ-8, sICAM-1 и ЭТ-1 зависели от степе-ни алкогольного фиброза печени и во 2-й груп-пе были выше, чем в 1-й (p0,05). В обеих груп-пах у пациентов с генотипом СА rs699947C2578A уровень VEGF-A был выше, чем упациентов с генотипом АА (р=0,04 и р=0,01,соответственно). У пациентов 2-й группы гено-тип ТТ rs281437 -451C>T ассоциировался сболее высоким уровнем sICAM-1 по сравнениюс таковым у пациентов с генотипом СС (р=0,05).Заключение. Прогрессирование фиброзапечени сопровождается изменением интерлей-кинового профиля и маркеров эндотелиальнойдисфункции, которые прямо связаны с плот-ностью печени

Взаимосвязь вариантов полиморфных локусов генов IL-6 (RS1800795)и IL-8 (RS4073)с уровнем соответствующих цитокинов в сыворотке крови при остром алкогольном гепатит

The article presents the peculiarities of the influence of polymorphic loci of the promoter regions of cytokine genes on the level of cytokines involved in the development of acute alcoholic hepatitis (AAH). Material and methods. 51 patients abusing alcohol were included in the study (mean age 50.1±9.1 years, 38 (78%) men). Two groups were formed: the comparison group (n=24) included patients, who were abusing alcohol, without somatic pathology, and the observation group AAH (n=27). In 44 patients (CG-24, AAH-20), concentrations of IL-6, IL-8 and allelic variants of polymorphic loci of the IL-6 interleukin genes (rs1800795), IL-8 (rs4073) were determined. Results. The levels of IL-6, IL-8 were significantly increased in patients with AAH compared with the patients from the comparison group. IL-6 correlates with ESR, IL-8 correlates with C-reactive protein. In patients with AAH, an association of the C allele, the CC and CG genotypes of the rs1800795 locus with an increased level of IL-6 was detected, with no differences in frequency between the groups. An association of the rs4073 T allele with the risk of developing the disease and a high level of IL-8 was detected. Conclusion. An acute inflammatory process in the liver is accompanied by an increase in interleukins, which correlate with the general indicators of inflammation. Carriage of the rs4073 T allele is associated with the risk of AAH and high IL-8 levels in these patients. Carrier rs1800795 locus C allele is associated with high levels of IL-6 in AAH.В статье представлены результаты изучения особенностей влияния полиморфных локусов промоторных областей генов цитокинов на уровень цитокинов, участвующих в развитии острого алкогольного гепатита (ОАГ). Материал и методы. Включен 51 пациент (средний возраст 50,1±9,1 лет, 38 (78%) мужчин), злоупотребляющих алкоголем. Были сформированы 2 группы: группа сравнения (n=24) - лица, злоупотребляющие алкоголем, без соматической патологии и группа наблюдения - ОАГ (n=27). У 44 пациентов (ГС-24, ОАГ-20) определяли концентрации IL-6, IL-8 и аллельные варианты полиморфных локусов генов интерлейкинов IL-6 (rs1800795), IL-8 (rs4073). Результаты. Уровни IL-6, IL-8 достоверно повышались при ОАГ по сравнению с группой сравнения. IL-6 коррелирует с уровнем СОЭ, IL-8 коррелирует с уровнем С-реактивного белка. У пациентов с ОАГ выявлена связь аллеля С, генотипов СС и CG локуса rs1800795 с повышенным уровнем IL-6, без различий по частоте между группами. Выявлена ассоциация аллеля Т локуса rs4073 с риском развития заболевания и высоким уровнем IL-8. Заключение. Острый воспалительный процесс в печени сопровождается повышением интерлейкинов, которые коррелируют с общими показателями воспаления. Носительство аллеля Т локуса rs4073 связано с риском развития ОАГ и высокого уровня IL-8 у данных пациентов. Носительство аллеля С локуса rs1800795 связано с высокими уровнями IL-6 при ОАГ

Serum level of IL‐8 and polymorphic locus rs4073 ‐352 a / t of the IL‐8 gene with alcoholic hepatitis

To study the serum level of interleukin-8 (IL-8) and the polymorphic locus rs4073 -352 A/T of the IL-8 gene (IL-8) in patients with alcoholic hepatitis (AH), depending on the severity of the disease

PNPLA3 rs738409 associates with alcoholic liver cirrhosis but not with serum levels of IL6, IL10, IL8 or CCL2 in the Russian population

Introduction and aim: Polymorphic variant rs738409 within the PNPLA3 gene associates with alcoholic liver cirrhosis (ALC) in heavy drinkers of various ancestry but has not yet been established in the Russian population characterized by high incidence of ALC. PNPLA3 rs738409 involvement in the inflammatory process has been proposed as one of the mechanisms of liver dysfunction. Relationship between the PNPLA3 polymorphism and the biochemical markers of inflammation in patients with ALC remains unclear. The current study revealed the association between the rs738409 polymorphism, liver cirrhosis and serum cytokines in heavy drinkers in the Russian population. Materials and methods: The serum levels of IL6, IL10, IL8, and CCL2 along with PNPLA3 rs738409 polymorphism were determined in heavy drinkers (AA, n = 71) and heavy drinkers with diagnosed liver cirrhosis (ALC, n = 110). All of the recruited individuals were Caucasians and belonged to the Russian population. Results: Heavy drinkers carrying PNPLA3 rs738409 CG or CG+GG genotypes as compared with CC genotype carriers or G allele as compared with C allele carriers had significant risk of ALC. In ALC levels of interleukins and CCL2 increased as compared with AA. PNPLA3 rs738409 CC carriers had lower cirrhosis stage as compared with CG+GG carriers, however there were no differences of IL6, IL10, IL8 or CCL2 levels between G allele carriers and non-carriers in heavy drinkers. Conclusion: Thus, in the Russian population heavy drinkers carrying PNPLA3 rs738409 G allele are at higher risk of ALC, however the presence of rs738409 allele does not influence the serum cytokine levels. © 2020 Fundación Clínica Médica Sur, A.C

Association of SNPs in the Promoter Regions of VEGF (rs699947 и rs2010963), ICAM1 (rs281437) and ET-1 (rs1800541) with Serum Levels of Related Proteins and Alcoholic Liver Cirrhosis Risk [Взаимосвязь полиморфных локусов, расположенных в промоторных областях генов VEGF (rs699947 и rs2010963), ICAM1 (rs281437) и ET-1 (rs1800541), с уровнем соответствующих белковых продуктов в сыворотке крови и риском развития алкогольного цирроза печени]

BACKGROUND: Uncontrolled use of alcohol can lead to the development of cirrhosis of the liver, which is manifested by fibrosis with the formation of regenerative nodes, an increase in pressure in the portal vein system and impaired liver function. Hepatic endothelium dysfunction during the formation of portal hypertension is accompanied by an increase in the level of protein molecules involved in the functioning of the endothelium: vascular endothelial growth factor A (VEGF-A), a soluble form of the intercellular adhesion molecule (s-ICAM-1) and endothelin-1 (ET -one). It is assumed that elevated levels of VEGF-A, s-ICAM-1 and ET-1 in alcoholic liver cirrhosis (AHC) may be interconnected with the structure of polymorphic loci, the promoter regions of the respective genes, which in turn may be a genetic risk factor for developing cirrhosis. AIMS: Investigate the relationship of carriage of variant forms of polymorphic loci located in the promoter regions of VEGF-A, ICAM-1 and ET-1 with the level of the corresponding proteins in the blood serum and the risk of AHC. MATERIALS AND METHODS: The main group consisted of patients with pathological dependence on alcohol, aggravated by cirrhosis of the liver (AHC, n=60). The control group consisted of persons suffering from alcohol abuse, without liver pathology (AA, n=24). The observation period was the period of hospitalization. The serum levels of VEGF-A, s-ICAM-1 and ET-1 were evaluated by enzyme immunoassay. The distribution of variant forms of polymorphic loci located in the promoter regions of the VEGF-A genes (rs699947 and rs2010963), ICAM1 (rs281437) and ET-1 (rs1800541) in the studied sample was performed by real-time PCR. RESULTS: The development of alcoholic cirrhosis was accompanied by a significant increase in the concentration of VEGF-A, s-ICAM-1 and ET-1 in serum. At the same time, direct correlations between the concentrations of VEGF-A, s-ICAM-1 and ET-1 in serum and the diameter of the portal vein in persons with liver cirrhosis were revealed. Patients with AHC are often carriers of the G allele of rs1800541 locus, located in the promoter of the ET-1 gene, compared with individuals suffering from control without liver pathology, which is associated with an increased risk of developing cirrhosis in alcohol dependence. The carriage of the C allele rs699947, as well as the C allele rs2010963 located in the promoter of the VEGF gene was associated with an increased level of VEGF-A in the AHC compared to carriers of this allele in the AA group. In addition, in the group of patients with AHC, carriers of allele C, homozygous CC genotype and heterozygous GC genotype of rs2010963 locus compared with carriers of G allele or homozygous GG genotype, respectively, were characterized by elevated serum VEGF-A levels. CONCLUSION: Carrier allele G of the rs1800541 locus (ET-1) is a risk factor for liver cirrhosis with alcohol abuse. The carriage of the C allele rs699947, as well as the C allele rs2010963 located in the promoter of the VEGF gene, can determine the elevated serum VEGF-A level in the AHC. © 2018 Izdatel'stvo Meditsina. All rights reserved