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Relationship between rs1799998 CYP11B2 gene polymorphism and left ventricular diastolic function in patients with chronic heart failure

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  • Save American Journal of Medicine and Medical Sciences 2021, 11(8): 598-601 DOI: 10.5923/j.ajmms.20211108.11 Association of the Polymorphism rs1799998 CYP11B2 Gene with Left Ventricular Diastolic Function in Patients with Chronic Heart Failure Nuritdinov N. A. Tashkent Medical Academy, Tashkent, Uzbekistan Abstract The aim of our study was to evaluate the role of polymorphism rs1799998 CYP11B2 gene in patients with chronic heart failure (CHF). In patients with CHF 152 Uzbeks have been studied the alleles and genotypes rs1799998 CYP11B2 gene. A relationship has been established between the carriage of the homozygous T / T genotype of the rs1799998 polymorphism of the CYP11B2 gene with an almost twofold increase in the risk of the formation of a restrictive form of CHF, which allows us to make an assumption, regarding this genotypic variant, about its prognostic role in increasing the risk of developing this form of CHF. Keywords Chronic heart failure, rs1799998 CYP11B2, Gene 1. Introduction Chronic heart failure (CHF) is not only a medical, but also a social problem due to the significant prevalence, high mortality rate and high costs of treating patients with CHF. It is expected that in the next 20-30 years the prevalence of CHF will increase by 40-60% [1]. An increase in the activity of the sympathetic-adrenal system (SAS) and the renin-angiotensin-aldosterone system (RAAS) and other neurohormones, mediators, including cytokines, endothelin, natriuretic peptide system plays a leading role in the pathogenesis of CHF [2]. There are circulating and tissue RAAS in the body. The circulating RAAS (10-15%) as a "quick" response system provides a short-term influence and control over the cardiovascular system (CVS), and the tissue RAAS is a system of long-term regulation. Adaptive-compensatory reactions at the initial stage of CHF development are provided mainly by the circulating RAAS. With prolonged activation in CHF, tissue RAAS is also significantly activated, including myocardial and renal [3]. If the main link of the RAAS is angiotensin II (AT II), then aldosterone is an equally important link and its adverse effects, in many respects similar to the effects of AT II. The secretion of aldosterone is influenced by AT II, sodium and potassium levels, ACTH, vasopressin, natriuretic peptide and endothelin. Aldosterone is synthesized not only in the adrenal cortex, but also in the myocardium and in the * Corresponding author: (Nuritdinov N. A.) Received: Aug. 15, 2021; Accepted: Aug. 26, 2021; Published: Aug. 30, 2021 Published online at vascular endothelium. Aldosterone promotes tissue fibrosis through several mechanisms: induction of inflammation and fibrinoid necrosis of small arteries and arterioles; effects on the corresponding receptors localized in the cytosol of vascular fibroblasts; stimulation of apoptosis of cardiomyocytes [4,5]. Aldosterone synthetase is a human enzyme encoded by the CYP11B2 gene (cytochrome P450, family 11, subfamily B, polypeptide 2) on chromosome 8. Aldosterone synthase belongs to the cytochrome P450 superfamily and provides the synthesis of the hormone aldosterone. The gene for aldosterone synthetase is mapped to chromosome 8 at q24.3. It is located next to the 11beta-hydroxylase gene (CYP11B1). The CYP11B2 gene is highly homologous to the CYP11B1 gene encoding 11-beta-hydroxylase. Despite significant research efforts, it is still unclear how the C-344T polymorphism affects steroid biosynthesis at the molecular level. On chromosome 8q24, the genes encoding the aldosterone synthase CYP11B2 and 11B-hydroxylase CYP11B1 are located in close proximity [6]. The most fully investigated polymorphism of the aldosterone synthase gene, which manifests itself in the substitution of cytosine for thymine at the 344th position of the nucleotide sequence, in the regulatory region of the gene. This site is the binding site for the steroidogenic transcription factor SF-1, which regulates the expression of the aldosterone synthase gene. According to recent studies, the T allele leads to an increase in aldosterone production, which in turn is associated with hypertension, as well as with fibrosis and myocardial hypertrophy and with the risk of hypertensive complications of pregnancy. A relationship was found between the aldosterone synthetase gene American Journal of Medicine and Medical Sciences 2021, 11(8): 598-601 599 polymorphism and the size, weight, and diastolic function of the LV in young people. The aldosterone synthase gene has been assigned to candidate genes in the development of cardiovascular remodeling [7,8]. The aim of our study was to association of the polymorphism rs1799998 CYP11B2 gene with left ventricular diastolic function in patients with chronic heart failure (CHF). Table 1. Expected and observed frequencies of distribution of alleles and genotypes of the CYP11B2 gene polymorphism (rs 1799998) in the group of patients with CHF Alleles Allele frequency Т 0.47 С 0.53 Genotype frequency Genotype Observed Ho Expected He χ2 p df Т/Т 0.25 0.22 0,8 2. Materials And Methods T/С 0.42 С/С 0.33 0.5 1.4 0.1 1 0.28 0.6 In patients with CHF 134 of Uzbek nationality have been Total 1.0 1.0 2.8 studied the genetic determinants of alleles and genotypes rs1799998 CYP11B2 gene. The control group consisted In the control group, allelic frequencies (T and C) of 102 healthy individuals— men of Uzbek nationality. corresponded to 0.51 and 0.49, while the observed The study was performed according to the standards of frequencies of the C / C, C / T, and T / T genotypes were 0.25; Good Clinical Practice (Good Clinical Practice) and the 0.52 and 0.23, and the expected ones are 0.26; 0.5 and 0.24, Declaration of Helsinki. The study protocol was approved by also with a statistically insignificant difference (χ2 = 0.16; the ethics committees of all participating clinical centers. p = 0.7). At the same time, the difference between the Before inclusion in the study all participants provided expected and observed frequencies of heterozygosity (D) written informed consent. All patients were divided into corresponded to +0.04. three groups of functional class (FC) of CHF according to the In the control group (n = 102), the proportion of carriage New York Heart Classification (NYHA) according to the test of the frequencies of the C and T alleles was 51.5% (n = 105) of 6-minute walk: the first group consisted of 31 patients and 48.5% (n = 99). At the same time, carriage of C / C and C with CHF FC I, the second group 62 patients with FC II and / T genotypes was detected in 25.5% (n = 26) and 52.0% (n = 3 group — 59 patients with FC III classification NYHA. 53) cases. At the same time, it is important to point out that in Study polymorphism rs198389 NPPB gene was conducted this group, cases of carriage of a functionally unfavorable using polymerase chain reaction on programmable genotype T / T were also recorded, which amounted to thermocycler CG-1–96 «Corbett Research» (Australia) and 22.5% (n = 23). 2720 «Applied Biosystems» (USA), using kits LLC “Medlab” At the same time, the frequencies of the C and T alleles in (St. Petersburg), according to the manufacturer’s instructions. the main group of patients with CHF (n = 134) had slightly In our work allele polymorphism G/T894 revealed after different values, namely, they were registered in 46.6% (n = digestion of the amplified fragment of 206 bp containing the 125) and 53.4% (n = 143) cases. In addition, with respect to polymorphic site. Evaluation of deviation of the distribution the frequency of the C / C genotype, almost the same of genotypes of studied polymorphisms of DNA from the proportion was established, corresponding to 25.4% (n = 34). canonical distribution of Hardy-Weinberg equilibrium was However, a slightly larger proportion compared to the performed using the computer program for the analysis of control was recorded among carriers of the C / T (42.5%, n = genetic data “GenePop” (“Genetics of Population”). To 57) and T / T (32.1%, n = 43) genotypes, which indicates a calculate the “odds ratio” (OR — odds ratio) with 95% possible role of functionally heterozygous (C / T) and mutant confidence intervals (CI— confidenceinterval), χ2 and (T / T) genotypes of CYP11B2 gene polymorphism pvalues used statistical package statistical software package (rs1799998) in the development of CHF. «OpenEpi 2009, Version 2.3». Thus, in the main group of CHF patients, compared with the control group, the T allele was 1.2 times more frequent (53.4% versus 48.5%; χ2 = 1.1; p = 0.3; OR = 1.2; 95% CI: 3. Results 0.84-1.74). At the same time, in relation to the frequencies of the C / C genotypes (25.4% versus 25.5%; χ2 <3.85; p> 0.05; Analysis of the frequency distribution of the genotypes of OR = 1.0; 95% CI: 0.55-1.8) and C / T (42.5% versus 52.0%; the rs 1799998 polymorphism of the CYP11B2 gene in the χ2 = 2.1; p = 0.1; OR = 0.7; 95% CI: 0.41-1.15) significant group of CHF patients showed a congruence for RHV. In differences were not found. Whereas in relation to the T / T particular, the frequencies of the C and T alleles were 0.47 genotype among patients with CHF, there was a pronounced and 0.53, while the observed frequencies of the C / C, C / T tendency to an increase in its frequency by 1.6 times (32.1% and T / T genotypes corresponded to 0.25; 0.42 and 0.33, and versus 22.5%; χ2 = 2.6; p = 0.1; OR = 1.6; 95% CI: their expected frequencies were 0.22; 0.5 and 0.28 with a 0.90-2.93). statistically insignificant difference (χ2 = 2.8; p = 0.1) and a The study of the distribution of the genotypes of the heterozygosity index (D) equal to -0.16 (Table 1). rs1799998 polymorphism of the CYP11B2 gene in various 600 Nuritdinov N. A.: Association of the Polymorphism rs1799998 CYP11B2 Gene with Left Ventricular Diastolic Function in Patients with Chronic Heart Failure types of left ventricular diastolic dysfunction (LVDD) in patients with CHF (with impaired relaxation, pseudonormal and restrictive) made it possible to identify their frequencies in CHF with impaired relaxation (n = 52) recorded in 32.7% (n = 17) for the C / C genotype, in 40.4% (n = 21) for the C / T genotype, and in 26.9% (n = 14) cases for the T / T genotype. The proportion of carriage of these genotypes in pseudonormal LVDD CHF (n = 45) was 24.4% (n = 11), 44.4% (n = 20) and 31.1% (n = 14) of the cases, respectively, and in the restrictive type of LVDD CHF (n = 37 ) - 16.2% (n = 6), 43.2% (n = 16) and 40.5% (n = 15) cases, respectively. In accordance with these data, there is a decrease in the frequency of the C / C genotype and, on the contrary, an increase in the frequency of the T / T genotype in the following pattern: CHF with impaired relaxation> CHF pseudonormal> CHF restrictive and CHF with impaired relaxation

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