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

Oxidative stress in the alcoholic liver disease

Parameters reflecting oxidative stress (OS) have been studied in 37 patients with alcoholic liver disease (ALD) during admission to the hospital and 2 weeks after the beginning of therapy. The patients were divided into 3 groups: alcoholic hepatitis (AH), alcoholic cirrhosis with hepatic insufficiency (the group C by the Child-Paquet scale) and terminal stage patients (subsequently died). All patients were characterized by a significant increase in plasma products of lipid peroxidation (conjugated diene and malondialdehyde) and a decrease of the ceruloplasmin level. The coefficient C OS significantly exceeded normal values both on admission and after the 2-week course of traditional therapy. This suggests an important role of the OS with ALD. © 2014 Pleiades Publishing, Ltd

Oxidative stress in the alcoholic liver disease

Parameters reflecting oxidative stress (OS) have been studied in 37 patients with alcoholic liver disease (ALD) during admission to the hospital and 2 weeks after the beginning of therapy. The patients were divided into 3 groups: alcoholic hepatitis (AH), alcoholic cirrhosis with hepatic insufficiency (the group C by the Child-Paquet scale) and terminal stage patients (subsequently died). All patients were characterized by a significant increase in plasma products of lipid peroxidation (conjugated diene and malondialdehyde) and a decrease of the ceruloplasmin level. The coefficient C OS significantly exceeded normal values both on admission and after the 2-week course of traditional therapy. This suggests an important role of the OS with ALD. © 2014 Pleiades Publishing, Ltd

Blood Content of Markers of Inflammation and Cytokines in Patients With Alcoholic Cardiomyopathy and Ischemic Heart Disease at Various Stages of Heart Failure

We conducted a comparative study of content proinflammatory cytokines, biomarkers of inflammatory process, biochemical indicators of congestive heart failure (CHF) and hemodynamic parameters in patients with alcoholic cardiomyopathy (ACMP) and ischemic heart disease (IHD) with various NYHA classes. We examined 62 men with ACMP (n = 45) and IHD (n = 17) and NYHA class III-IV CHF. Patients of both groups had lowered ejection fraction (EF), dilated cardiac chambers, and increased left ventricular (LV) myocardial mass index (MMI). Relative LV wall thickness was within normal limits but in the ACMP group it was significantly lower than in IHD group what corresponded to the eccentric type of myocardial hypertrophy. Higher NYHA class was associated with lower EF and larger end diastolic and end systolic LV dimensions. In ACMP it was also associated with larger dimension of the right ventricle while in IHD with substantially larger (by 30%) dimension of atria. Substantial amount of endotoxin found in blood plasma of patients with IHD corresponded to the conception of increased intestinal permeability of in CHF. Alcohol abuse was an aggravating factor of endotoxin transmission and its concentration in patients with ACMP was 3 times higher than in patients with IHD. Patients with ACMP had substantially elevated blood concentrations of interleukins (IL) 6, 8, 12, tumor necrosis factor alpha (TNF-alpha), and its soluble receptor s-TNF-R; they also had twofold elevation of C-reactive protein concentration. ACMP was associated with manifold rise of blood content of brain natriuretic peptide (BNP). Patients with IHD also had elevated blood concentrations of IL 6, 8 and 12 but their values were 1.5-2 times lower than ACMP group. Blood content of TNF-alpha and s-TNF-R in IHD group was within normal limits. Higher NYHA class in ACMP patients was associated with higher concentrations of IL 6 and 8, TNF-alpha, and BNP. In both groups of patients contents of IL-12, s-TNF-R, TGF-1 beta and factors of acute phase of inflammation did not reflect severity of CHF. Functional insufficiency of myocardium in IHD patients was best characterized by blood content of IL-6 while in ACMP patients of BNP

Blood Content of Markers of Inflammation and Cytokines in Patients With Alcoholic Cardiomyopathy and Ischemic Heart Disease at Various Stages of Heart Failure

We conducted a comparative study of content proinflammatory cytokines, biomarkers of inflammatory process, biochemical indicators of congestive heart failure (CHF) and hemodynamic parameters in patients with alcoholic cardiomyopathy (ACMP) and ischemic heart disease (IHD) with various NYHA classes. We examined 62 men with ACMP (n = 45) and IHD (n = 17) and NYHA class III-IV CHF. Patients of both groups had lowered ejection fraction (EF), dilated cardiac chambers, and increased left ventricular (LV) myocardial mass index (MMI). Relative LV wall thickness was within normal limits but in the ACMP group it was significantly lower than in IHD group what corresponded to the eccentric type of myocardial hypertrophy. Higher NYHA class was associated with lower EF and larger end diastolic and end systolic LV dimensions. In ACMP it was also associated with larger dimension of the right ventricle while in IHD with substantially larger (by 30%) dimension of atria. Substantial amount of endotoxin found in blood plasma of patients with IHD corresponded to the conception of increased intestinal permeability of in CHF. Alcohol abuse was an aggravating factor of endotoxin transmission and its concentration in patients with ACMP was 3 times higher than in patients with IHD. Patients with ACMP had substantially elevated blood concentrations of interleukins (IL) 6, 8, 12, tumor necrosis factor alpha (TNF-alpha), and its soluble receptor s-TNF-R; they also had twofold elevation of C-reactive protein concentration. ACMP was associated with manifold rise of blood content of brain natriuretic peptide (BNP). Patients with IHD also had elevated blood concentrations of IL 6, 8 and 12 but their values were 1.5-2 times lower than ACMP group. Blood content of TNF-alpha and s-TNF-R in IHD group was within normal limits. Higher NYHA class in ACMP patients was associated with higher concentrations of IL 6 and 8, TNF-alpha, and BNP. In both groups of patients contents of IL-12, s-TNF-R, TGF-1 beta and factors of acute phase of inflammation did not reflect severity of CHF. Functional insufficiency of myocardium in IHD patients was best characterized by blood content of IL-6 while in ACMP patients of BNP

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