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

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Abstract


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.


Alexandr S. Ivanov

RUDN University

Author for correspondence.
Email: aleks_iv90@mail.ru
ORCID iD: 0000-0001-6850-0800

Russian Federation

MD, fellow student at the department of internal diseases with the course of cardiology and functional diagnostics named after V.S. Moiseev.

117292, Moscow, ul. Vavilova, 61

SPIN-код: 2352-6452

Irina V. Garmasch

RUDN University

Email: igarmasch@bk.ru
ORCID iD: 0000-0002-2950-3563

Russian Federation

MD, PhD, аssociate professor at the department of internal diseases with the course of cardiology and functional diagnostics named after V.S. Moiseev.

Moscow

SPIN-код: 3023-5147, SCOPUS ID 6602317703

Olga S. Arisheva

RUDN University

Email: olga.arisheva@yandex.ru
ORCID iD: 0000-0002-2964-0568

Russian Federation

MD, PhD, assistant of professor at the department of internal diseases with the course of cardiology and functional diagnostics named after V.S. Moiseev.

Moscow

SPIN-код: 7556-0455

Mariya A. Markova

RUDN University

Email: markova-maria@yandex.ru
ORCID iD: 0000-0001-6409-4075

Russian Federation

MD, PhD, associate professor at the department of internal diseases with the course of cardiology and functional diagnostics named after V.S. Moiseev.

Moscow

SPIN-код: 5862-6143

Anna S. Melnik

RUDN University

Email: ann-garmash@yandex.ru
ORCID iD: 0000-0002-4057-5058

Russian Federation

MD, student

Moscow

SPIN-код: 7672-4422

Natalya N. Terebilina

V. Serbsky National Medical Research Centre for Psychiatry and Narcology

Email: n.terebilina@mail.ru
ORCID iD: 0000-0002-5356-0728

Russian Federation

MD, PhD.

Moscow

SPIN-код: 3830-1244, SCOPUS ID 6506201841

Valeria Yu. Baronets

V. Serbsky National Medical Research Centre for Psychiatry and Narcology

Email: biochn@mail.ru
ORCID iD: 0000-0002-9715-4473

Russian Federation

MD, Senior Scientist of the laboratory of biochemistry.

Moscow

SPIN ID 7948-3499, SCOPUS ID 55404273600

Daniil I. Peregud

V. Serbsky National Medical Research Centre for Psychiatry and Narcology

Email: peregud_d@yahoo.com
ORCID iD: 0000-0002-2733-9640

Russian Federation

MD, PhD, Senior Scientist of the laboratory of biochemistry.

Moscow

SPIN ID 3572-9652, SCOPUS ID 23393721300

Ekaterina V. Tarasenko

RUDN University

Email: tarasenko_ev@inbox.ru
ORCID iD: 0000-0002-0665-9741

Russian Federation

MD, PhD, associate professor at the department of biology and general genetics.

Moscow

SPIN ID 7155-2735, SCOPUS ID 35550453900

Zhanna D. Kobalava

RUDN University

Email: kobalava_zhd@rudn.university
ORCID iD: 0000-0002-5873-1768

Russian Federation

MD, PhD, Doctor of science, professor, head of the department of internal diseases with the course of cardiology and functional diagnostics named after V.S. Moiseev.

Moscow

SPIN ID 9828-5409, SCOPUS ID 127565

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