Polymorphism of renin — angiotensin system genes in progression of liver fibrosis in patients with chronic hepatitis C

Aim of investigation. To estimate relation of polymorphism of genes encoding reninangiotensin system components (AGT G-6A, AGT M235T and ATR1 A1166C) with rate of liver fibrosis progression in patients with chronic hepatitis C (CHC).Material and methods. Overall 109 patients with CHC and liver cirrhosis C with established stage of fibrosis and duration of disease have been divided into group of «rapidly progressing fibrosis» (55 patients, ≥0,130 fibrosis points/year) and «slowly progressing fibrosis» (54 persons, <0,130 fibrosis units/year). Assessment of polymorphism of studied genes was carried out by molecular genetic methods.Results. In CHC patients of «rapidly progressing fibrosis» group in comparison to «slowly progressing fibrosis» group minor A-allele (50,0 and 33,3% respectively, p=0,0126) and «mutant» АА-genotype (27,3 and 11,1%, р=0,0324; OR АА=3,00; 95% CI 1,07-8,45), AGT gene on locus G-6A, as well as minor T-allele (р=0,0407) of AGT gene in M235T locus were significantly more common while MM genotype of M235T polymorphism of AGT gene (20,8 and 44,4%, respectively, p=0,0090; OR MM=0,33; 95%-CI 0,15–0,73) were significant less frequent. No significant differences between groups in distribution of alternative alleles and genotypes of ATR1 gene on A1166C locus have been revealed.Conclusion. Carriage of mutant alleles of angiotensinogen gene on any of loci (G-6A or M235T) is the factor predicting more rapid progression of disease. As chronic hepatitis C is multifactorial disease, it is rational to use testing of allelic variants of angiotensinogen gene in patient-specific approach at CHC management

Association of the AGT, ACE, NOS3 polymorphism with subclinical arterial wall changes and cardiovascular diseases risk factors

Background. Renin-Angiotensin-Aldosterone System activation (RAAS) and nitric oxide (NO) reduction lead to the changes in the arterial wall, which, in turn, create a favourable environment for the development of cardiovascular diseases (CVD). There is only limited knowledge of the influence of proteins participating in the RAAS activation and providing NO bioavailability on the parameters of the arterial wall state (pulse wave velocity (PWV), carotid artery intima-media thickness (cIMT), endothelium-dependent vasodilation (EDVD), presence of atherosclerotic plaques) and risk factors of CVD. Aim. Finding the association between the AGT, ACE, NOS3 polymorphism and PWV, cIMT, EDV, presence of atherosclerotic plaques and risk factors of CVD in healthy subjects. Methods. Using intergroup analysis and models of multiple logistic regression, we examined the association of AGT с.521СТ polymorphism, AСE InsDel polymorphism, NOS3 с.894GT polymorphism with arterial wall changes and risk factors of CVD in 160 healthy people of different ages. Results. The CT genotype of AGT с.521СТ polymorphism was associated with lower levels of systolic blood pressure (BP) (p=0.013) and central systolic BP (p=0.029), higher level of Insulin-Like Growth Factor (IGF) (p=0.027). The DD genotype of ACE InsDel polymorphism was associated with a higher waist/hip ratio (p=0.044), lower level of high density lipoprotein cholesterol (p=0.01), lower index of EDVD (p=0.042), higher incidence ofendothelial dysfunction (ED) (p=0.026). The GG genotype of NOS3 с.894GT polymorphism was associated with higher levels of central systolic BP (p=0.022) and central mean BP (p=0.033), total cholesterol (p=0.025), low density lipoprotein cholesterol (p=0.014) and IGF (p=0.042), higher incidence of ED (p=0.007), albuminuria (p=0.032) and insulin resistance (p=0.03). Conclusion. We have found the association of the AСE and NOS3 polymorphism with endothelial dysfunction and the metabolic status

The role of genetic factors in the development of recurrent urolithiasis

Introduction. Urolithiasis is a polyethylological disease of the urinary system. Epidemiological data on urolithiasis is disappointing: over the past 30 years, the number of patients with urolithiasis has increased by 48.57%, and the mortality rate has increased by 17.12%. Single nucleotide polymorphisms in various genes can influence the risk of development and recurrence of this disease. Early diagnosis of a patient's genetic predisposition to primary or recurrent urolithiasis is important for the effective prevention of urolithiasis.Objective. To explore the association of SNP (Single Nucleotide Polymorphism) rs3134057 (TNFRS11B), rs851982 (ESR1), rs1540339 (VDR), rs2202127 (CASR), rs526906 (KL) with the development of recurrent urolithiasis.Materials and methods. The observed group consisted of 96 patients with a single-sided ureteral stone, of whom 45 had recurrent urolithiasis; the control group consisted of 51 volunteers. Venous blood samples were collected from all participants, DNA was extracted from the blood and analyzed for each SNP studied by real-time polymerase chain reaction. We analyze the data obtained on genotype and presence or absence of urolithiasis in the participants using a binomial logistic regression model.Results. An association was found between the presence of SNP rs3134057 in the TNFRS11B gene (odds ratio (OR), 1.92; confidence interval (CI): 1.05-3.52; p = 0.031) and the development of recurrent urolithiasis.Conclusion. The association of rs3134057 with urolithiasis relapse leads us to investigating the effect of this SNP on serum osteoprotegerin levels, a product of the TNFRS11B gene

Steroid pulse -therapy in patients With coronAvirus Pneumonia (COVID-19), sYstemic inFlammation And Risk of vEnous thRombosis and thromboembolism (WAYFARER Study)

Introduction: Coronavirus pneumonia not only severely affects the lung tissue but is also associated with systemic autoimmune inflammation, rapid overactivation of cytokines and chemokines known as “cytokine storm”, and a high risk of thrombosis and thromboembolism. Since there is no specific therapy for this new coronavirus infection (COVID-19), searching for an effective and safe anti-inflammatory therapy is critical.Materials and Methods: This study evaluated efficacy and safety of pulse therapy with high doses of glucocorticosteroids (GCS), methylprednisolone 1,000 mg for 3 days plus dexamethasone 8 mg for another 3-5 days, in 17 patients with severe coronavirus pneumonia as a part of retrospective comparative analysis (17 patients in control group). The study primary endpoint was the aggregate dynamics of patients’ condition as evaluated by an original CCS-COVID scale, which included, in addition to the clinical status, assessments of changes in the inflammation marker, C-reactive protein (CRP); the thrombus formation marker, D-dimer; and the extent of lung injury evaluated by computed tomography (CT). Patients had signs of lung injury (53.2 % and 25.6 %), increases in CRP 27 and 19 times, and a more than doubled level of D-dimer (to 1.41 µg/ml and 1.15 µg/ml) in the active therapy and the control groups, respectively. The GCS treatment group had a more severe condition at baseline.Results: The GCS pulse therapy proved effective and significantly decreased the CCS-COVID scores. Median score difference was 5.00 compared to the control group (р=0.011). Shortness of breath considerably decreased; oxygen saturation increased, and the NEWS-2 clinical status scale scores decreased. In the GCS group, concentration of CRP significantly decreased from 134 mg/dl to 41.8 mg/dl (р=0.009) but at the same time, D-dimer level significantly increased from 1.41 µg/ml to 1.98 µg/ml (р=0.044). In the control group, the changes were nonsignificant. The dynamics of lung injury by CT was better in the treatment group but the difference did not reach a statistical significance (р=0.062). Following the GCS treatment, neutrophilia increased (р=0.0001) with persisting lymphopenia, and the neutrophil/lymphocyte (N/L) ratio, a marker of chronic inflammation, increased 2.5 times (р=0.006). The changes in the N/L ratio and D-dimer were found to correlate in the GCS pulse therapy group (r =0.49, p=0.04), which underlined the relationship of chronic autoimmune inflammation with thrombus formation in COVID-19. No significant changes were observed in the control group. In result, four patients developed venous thromboembolic complications (two of them had pulmonary artery thromboembolism) after the GCS pulse therapy despite the concomitant antiplatelet treatment at therapeutic doses. Recovery was slower in the hormone treatment group (median stay in the hospital was 26 days vs 18 days in the control group, р=0.001).Conclusion: Pulse therapy with high doses of GCS exerted a rapid anti-inflammatory effect but at the same time, increased the N/L ratio and the D-dimer level, which increased the risk of thromboembolism

ASSOCIATION OF MOLECULAR GENETIC FACTORS WITH THE SIGNS OF ATEROSCLEROTIC PLAQUES INSTABILITY

Aim. Analysis of possible associations of polymorphisms of the urokinase system and matrix metalloproteases genes with criteria of atherosclerotic plaques instability.Material and methods. Totally, 50 patients were investigated, with carotid atherosclerosis (32 males and 18 females). Inclusion criteria were carotid stenosis ≥70% and carotid endarterectomy. Patients were selected to groups according to macroscopic signs of instability of the lesions and thickness of fibrous cap. The groups were compared by the rates of mononucleotide polymorphisms С(-1306)Т (rs243865) gene MMP2, С(-1562)T (rs3918242) and A855G (Gln279Arg, rs17576) gene MMP9, Pro141Leu (C7240T, rs2227564) and С/T 3′-UTR (rs4065) gene PLAU, Lys220Arg (A659G, rs2302524) and T(-516)C (rs344781) gene PLAUR, (-675)4G/5G (rs1799768)gene SERPINE1.Results. Monofactorial analysis showed the association of the variants 279Gln/Gln of gene MMP9 and 141Leu/Leu gene PLAU with development of macroscopically stable plaques. By multifactorial analysis, only the carriage of genotype 141Leu/Leugene PLAU was associated with development of stable plaques. For the group of genotype carriers 141Pro/Leu and 141Leu/Leu odds ratio is 0,22 (95% confidence interval 0,05-0,93). With the development of plaques with capsule less than 65 mcm, by monofactorial analysis, the associated variants are 3′-UTR C/T gene PLAU and (-516)T/C gene PLAUR, and normal body mass. Presence of obesity and the carriage of allele (-516) C gene PLAUR are protective against the thin cap plaques development. In patients with absent obesity and genotype (-516)T/T gene PLAUR odds ratio for the thin cap plaque occurrence is 10,16 (95% confidence interval 2,5740,16).Conclusion. In the work, an association is shown of the polymorphism of urokinase system gene (urokinase plasminogen activator and receptor) with criteria of atherosclerotic lesion instability. Also, an association demonstrated of obesity with more stable plaques

Association of gene polymorphisms of the reninangiotensin system and endothelial dysfunction with development and severity of portal hypertension in patients with chronic hepatitis C

Background: At present, much attention is paid to genetic factors explaining the clinical course of chronic hepatitis C. Aim: To evaluate an association of the gene polymorphisms involved in the formation of endothelial dysfunction (NOS3 894G/T, CYBA 242C/T, MTHFR 677C/T) and encoding components of the renin-angiotensin system (ATR1 1166A/C, AGT (-6)G/T and 235M/T) with development and severity of portal hypertension syndrome in patients with chronic hepatitis C. Materials and methods: 162 patients with chronic hepatitis C and HCV-related cirrhosis (114 women and 48 men) were divided into the following groups: no portal hypertension (n = 98), "compensated" (n = 19) and "decompensated" (n = 45) portal hypertension. The gene polymorphisms were assessed by molecular genetic methods. Results: TT genotype of CYBA was more common in patients with portal hypertension than in those without (odds ratio (OR) for TT = 3.59, p = 0.031). This difference becomes larger when comparing the decompensated portal hypertension group with the no portal hypertension group (OR TT = 5.46, p = 0.009). Other gene polymorphisms were not associated with development or decompensation of portal hypertension. Multivariate analysis of the impact of genetic, clinical and demographic factors showed that portal hypertension was associated primarily with patients age at the time of the study (Wald's х2 = 14.99) and with their body mass index (Wald's х2 = 4.35). After exclusion of these population-wide risk factors from the model, the development of portal hypertension correlated with the carriage of 235TT genotype of CYBA (Wald's х2 = 6.07, OR = 4.29) and (-6)AA genotype AGT (Wald's х2 = 4.73, OR = 4.13), as well as with the lack of protective 235TT genotype AGT (Wald's х2 = 4.06, OR = 0.33). The combined effects of the studied gene polymorphisms on decompensation of the portal hypertension in patients with chronic HCV infection were similar. Conclusion: The development and increase in severity of portal hypertension syndrome in patients with chronic hepatitis C is directly correlated with the carriage of AA genotype of AGT (-6)G/A and TT genotype CYBA 242C/T and the absence of TT genotype AGT 235M/T

The clinical role of blood coagulation and platelet receptors gene allelic variants in development of Wilson’s disease

Aim of investigation. To estimate the effect of carriage of various allelic variants of blood coagulation system and platelet receptors genes on Wilson’s disease (WD) clinical presentation features. Material and methods. Original study included 85 patients with a Wilson’s disease who were divided into two groups: without neurological symptoms (abdominal form; n=51) and with neurologic symptomatology (mixed form; n=34). Genetic polymorphism testing was carried out by real-time polymerase chain reaction with melting curve analysis. Results. Alleles A of hemostasis genes FII 20210 G/A, FV 1691G/A were more frequent in the group with neurologic symptomatology as compared to the group of patients with abdominal form of WD at the level of trend. Frequency of 5G allele of plasminogen activator inhibitor gene PAI-675 5G/4G in the group with neurologic symptoms was lower (41.17%), than in the group without symptoms of central nervous system (CNS) involvement (49.02%) (odds ratio - OR: 1.374; 95% confidence interval - CI: 0.739-2.553). In the group of patients with neurological symptoms 4G4G genotype of PAI-675 5G/4G gene was more common (47.06%), than in patients without those symptoms (23.53%) (OR: 2.889; 95%-CI: 1.135-7.350). The allele T of platelet receptor gene ITGA2 807 C/T was more common in patients with CNS involvement than in the group of patients without neurological symptoms (р =0.018; OR: 2.172. 95%-CI: 1.163-4.058). Integrated genotype CT+TT was significantly more common in patients with neurological symptoms (82.35%) as compared to patients without those (54.90%) (р =0.010; OR: 3,833; 95%-CI: 1.355-10.846). Conclusion. Carriage of mutant genotypes FII 20210 G/A, FV 1691G/A, PAI-675 5G/4G, ITGA2 807 C/T is the factor associated to the presence of neurological symptoms at Wilson's disease

Prognostic role of hemostasis-regulating genetic factors and their interaction with conventional risk factors at the early stages of coronary heart disease development

Aim. To investigate the prognostic role of selected single nucleotide polymorphisms in hemostasis-regulating genes and to clarify their interaction with conventional risk factors, RF (smoking, arterial hypertension (AH), hypercholesterolemia (HCH), obesity (O)) at the early stages of coronary heart disease (CHD) development, with or without subsequent myocardial infarction (MI). Material and methods. The study included 977 men aged 20–55 years: 375 CHD patients (189 and 186 with or without previous MI, respectively) and 602 individuals without cardiovascular disease (CVD). Exclusion criteria were diabetes mellitus and impaired glucose tolerance. The authors analysed the polymorphisms of thrombocyte receptor genes GPIa (C807T) and GPIIIa (PLA1/PLA2); coagulation and fibrinolytic protein genes for factor VII (R353Q) and factor XIII (V34L); and the plasminogen activator inhibitor-1 (PAI-1) 4G/5G polymorphism. The association of these polymorphisms with conventional RF (smoking, AH, HCH, and O) was also investigated. To identify genetic variations, a restriction fragment length polymorphism assay, allele-specific assay, and fluorescence primer-probe assay were used. Results. Increased CHD risk was associated with the TT genotype of GPIa (p=0,0001; OR=10,2). The LL genotype of FXIII (p=0,03; OR=0,48) and QQ genotype of FVII (p=0,01; OR=0,12) were linked to reduced CHD risk. The combination of FXIII L allele and FVII Q allele was associated with a lower MI risk in CHD patients (p=0,03; OR=0,33). In participants with HCH, the PLA2/PLA2 genotype of GPIIIa was linked to increased MI risk for CHD patients (p=0,01; OR=6,0). Conclusion. The algorithm for predicting the genetic CHD risk may incorporate the assessment of the genetic polymorphism of GPIa (C807T), GPIIIa (PLA1/PLA2), factor XIII (V34L), and factor VII (R353Q). The study results did not confirm the negative effect of the PAI-1 gene 4G/5G polymorphism on CHD risk

The clinical role of blood coagulation and platelet receptors gene allelic variants in development of Wilson’s disease

Aim of investigation. To estimate the effect of carriage of various allelic variants of blood coagulation system and platelet receptors genes on Wilson’s disease (WD) clinical presentation features. Material and methods. Original study included 85 patients with a Wilson’s disease who were divided into two groups: without neurological symptoms (abdominal form; n=51) and with neurologic symptomatology (mixed form; n=34). Genetic polymorphism testing was carried out by real-time polymerase chain reaction with melting curve analysis. Results. Alleles A of hemostasis genes FII 20210 G/A, FV 1691G/A were more frequent in the group with neurologic symptomatology as compared to the group of patients with abdominal form of WD at the level of trend. Frequency of 5G allele of plasminogen activator inhibitor gene PAI-675 5G/4G in the group with neurologic symptoms was lower (41.17%), than in the group without symptoms of central nervous system (CNS) involvement (49.02%) (odds ratio - OR: 1.374; 95% confidence interval - CI: 0.739-2.553). In the group of patients with neurological symptoms 4G4G genotype of PAI-675 5G/4G gene was more common (47.06%), than in patients without those symptoms (23.53%) (OR: 2.889; 95%-CI: 1.135-7.350). The allele T of platelet receptor gene ITGA2 807 C/T was more common in patients with CNS involvement than in the group of patients without neurological symptoms (р =0.018; OR: 2.172. 95%-CI: 1.163-4.058). Integrated genotype CT+TT was significantly more common in patients with neurological symptoms (82.35%) as compared to patients without those (54.90%) (р =0.010; OR: 3,833; 95%-CI: 1.355-10.846). Conclusion. Carriage of mutant genotypes FII 20210 G/A, FV 1691G/A, PAI-675 5G/4G, ITGA2 807 C/T is the factor associated to the presence of neurological symptoms at Wilson's disease

The clinical role of blood coagulation and platelet receptors gene allelic variants in development of cryoglobulinemic vasculitis at chronic hepatitis C

Aim of investigation. To estimate the clinical and prognostic value of carriage of various blood coagulation and platelet receptors gene allelic variants in development of cryoglobulinemic vasculitis at chronic hepatitis C (CHC). Material and methods. Original study included overall 200 patients with CHCs and liver cirrhosis in its outcome, who were divided into 3 groups: patients without cryoglobulinemia (CG, n=123), those with asymptomatic cryoglobulinemia (ACG, n=40) and with cryoglobulinemic vasculitis (CGV, n=37). Assessment of polymorphism of the studied genes was carried out by real-time polymerase chain reaction with melting curve analysis. Results. CGV patients in comparison to those with ACG had 4G mutant allele are significantly more frequent (odds ratio (OR): 4G=2,008) as well as genotypes 5G4G+4G4G (OR: 5G4G+4G4G=4,950) of the gene PAI-675 5G/4G, and in comparison to patients without CG - CC mutant genotype of the gene ITGB3 1565 T/C (р =0,047). The multifactor analysis at comparison of patients with CGV and without it revealed the quantity of mutant alleles of PAI-675 5G/4G and ITGB3 1565 T/C genes and infection duration as independent factors for vasculitis development, while at comparison of patients with CGV and ACG - only quantity of mutant alleles of these genes. Patients with CGV allele C and CC homozygosity of the gene ITGB3 1565 T/C is associated to presence of renal diseases, while allele C genotypes (TC+CC) of ITGB3 1565 T/C gene is associated with involvement of muscular and nervous system. Conclusion. Carriage of mutant genotypes of PAI-675 5G/4G and ITGB3 1565 T/C genes is a factor which allows to predict CGV development in CHC patients, and can determine clinical manifestations of the latter