Study on rs1799998 polymorphism of CYP11B2 and rs198389 NPPB gene in patients with chronic heart failure
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https://www.eduzhai.net American Journal of Medicine and Medical Sciences 2021, 11(9): 611-614 DOI: 10.5923/j.ajmms.20211109.01 Study of the Gene rs1799998 of the CYP11B2 and rs198389 NPPB Polymorphism with Chronic Heart Failure Nuritdinov Nuriddin Anvarkhodjaevich1, Kamilova Umida Kabirovna2,* 1Tashkent Medical Academy, Tashkent, Uzbekistan 2Republican Specialized Scientific-Practical Medical Center of Therapy and Medical Rehabilitation, Tashkent, Uzbekistan Abstract The aim of our study was to evaluate the role of polymorphism genes rs1799998 of the CYP11B2 and rs198389 NPPB in patients with chronic heart failure (CHF). In patients with CHF 152 Uzbek nationality have been studied the alleles and genotypes genes rs1799998 CYP11B2 and rs198389 NPPB. T / T genotype of the polymorphic locus rs1799998 of the CYP11B2 gene plays a significant role in the formation of CHF and is a risk factor for the development of a severe course of the disease. The difference in the distribution of the NPPB gene (rs198389) frequency of the unfavorable C allele between the group of CHF patients and the control group was characterized by its clear increase among patients by 1.4 times and was accompanied an increase in the unfavorable genotypes T / C and C / C compared to those in the control group by 1.2 and 1.5 times. Keywords Chronic heart failure, Aldosterone synthase, B-type natriuretic peptide, Gene polymorphism 1. Introduction Chronic heart failure (CHF) is a widespread, progressive and prognostically unfavorable disease of the cardiovascular system, a serious cause of disability and a reduction in the life expectancy of the population of developed countries. According to the Framingham Study, its frequency doubles every decade, and in the next 20-30 years it will increase by 40-60%. The disease sharply worsens the quality of life of patients, increases the risk of mortality by 4 times, and the mortality rate of patients during the year is 15-50% . Identification of genetic risk factors for cardiovascular disease and to assess their contribution to the development of disease— one of the main problems of molecular cardiology. Genetic risk factors, as opposed to a clinical, biochemical, environmental and others . Testing of susceptibility genes allows, first of all, to form a group of persons of high cardiovascular risk for the purpose of therapeutic and preventive measures aimed at reducing the extent of the risk under the supervision of a physician. Identification of the genetic predisposition to any disease can be carried out well before the onset of clinical symptoms, which can effectively prevent its development or postpone deadlines demonstrations . However, molecular genetic testing can * Corresponding author: firstname.lastname@example.org (Kamilova Umida Kabirovna) Received: Aug. 23, 2021; Accepted: Sep. 6, 2021; Published: Sep. 10, 2021 Published online at https://www.eduzhai.net detect features of etiopathogenesis and course the most common cardiovascular disease in each patient. One of the most important pathogenetic mechanisms of CHF is the activation of a number of neurohormonal systems, among which SAS, RAAS, aldosterone (Al), vasopressin, the system of natriuretic peptides (NP), etc. are of particular importance. and some others . Aldosterone is involved in multiple mechanisms of CHF development, contributes to perivascular and intramyocardial fibrosis, a decrease in arterial wall compliance, an increase in the rate of remodeling of the heart chambers, an increase in the rigidity of their walls and, as a result, the development and progression of LV diastolic and systolic dysfunction, and always an increased synthesis of aldosterone has a negative effect on prognosis of patients . According to studies, the activity of the CYP11B2 gene polymorphism (rs1799998) is associated with a 4-fold increase in aldosterone production, an increased level of which directly correlates with unfavorable clinical outcomes among patients with heart failure . It has long been proven that in the development of cardiovascular disease in general and heart failure in particular, occupies a special place N-terminal pro-B-type natriuretic peptide. One of the genes, whose role in the development of heart failure has been widely discussed in recent years, is the gene of rs198389 polymorphism brainnatriuretic peptide (NPPB). Natriuretic peptide (NP), including B-type natriuretic peptide (BNP) and N-terminal 612 Nuritdinov Nuriddin Anvarkhodjaevich and Kamilova Umida Kabirovna: Study of the Gene rs1799998 of the CYP11B2 and rs198389 NPPB Polymorphism with Chronic Heart Failure pro-B-type natriuretic peptide (NT-proBNP), has been shown to be an effective biomarker not only for diagnosis but also for prognostic evaluation both for patients with heart failure HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) . Both BNP and NT-proBNP are released in a 1:1 ratio in the peripheral circulation. The predominant stimulus for synthesis and release of BNP from the atria and ventricles is thought to be wall stretch . The aim of our study was to evaluate the role of polymorphism genes rs1799998 CYP11B2 and rs198389 NPPB in patients with chronic heart failure (CHF). 2. Materials and Methods In patients with CHF 152 of Uzbek nationality have been studied the genetic determinants of alleles and genotypes rs1799998 CYP11B2 and rs198389 NPPB gene. The control group consisted of 75 healthy individuals— men of Uzbek nationality. The study was performed according to the standards of Good Clinical Practice (Good Clinical Practice) and the Declaration of Helsinki. The study protocol was approved by the ethics committees of all participating clinical centers. Before inclusion in the study all participants provided written informed consent. All patients were divided into three groups of functional class (FC) of CHF according to the New York Heart Classification (NYHA) according to the test of 6-minute walk: the first group consisted of 29 patients with CHF FC I, the second group 62 patients with FC II and 3 group — 59 patients with FC III classification NYHA. Study polymorphism rs1799998 CYP11B2 and rs198389 NPPB genes was conducted using polymerase chain reaction on programmable thermocycler CG-1–96 «Corbett Research» (Australia) and 2720 «Applied Biosystems» (USA), using kits LLC “Medlab” (St. Petersburg), according to the manufacturer’s instructions. In our work allele polymorphism G/T894 revealed after digestion of the amplified fragment of 206 bp containing the polymorphic site. Evaluation of deviation of the distribution of genotypes of studied polymorphisms of DNA from the canonical distribution of Hardy-Weinberg equilibrium was performed using the computer program for the analysis of genetic data “GenePop” (“Genetics of Population”). To calculate the “odds ratio” (OR — odds ratio) with 95% confidence intervals (CI— confidenceinterval), χ2 and pvalues used statistical package statistical software package «OpenEpi 2009, Version 2.3». 3. Results The study of the frequency distribution of the CYP11B2 gene (rs1799998) T and C alleles of the polymorphic variant of the in the control group (n = 102), the proportion of carriage of the frequencies of the C and T alleles was 51.5% (n = 105) and 48.5% (n = 99). At the same time, carriage of C / C and C / T genotypes was detected in 25.5% (n = 26) and 52.0% (n = 53) cases. At the same time, it is important to point out that in this group, cases of carriage of a functionally unfavorable genotype T / T were also recorded, which amounted to 22.5% (n = 23). At the same time, the frequencies of the C and T alleles in the main group of patients with CHF (n = 134) had slightly different values, namely, they were registered in 46.6% (n = 125) and 53.4% (n = 143) cases. In addition, with respect to the frequency of the C / C genotype, almost the same proportion was established, corresponding to 25.4% (n = 34). However, a slightly larger proportion compared to the control was recorded among carriers of the C / T (42.5%, n = 57) and T / T (32.1%, n = 43) genotypes, which indicates a possible role of functionally unfavorable heterozygous (C / T) and mutant (T / T) genotypes of CYP11B2 gene polymorphism (rs1799998) in the development of CHF. To identify the features of the distribution of allele frequencies and genotypes of CYP11B2 gene polymorphism (rs1799998) depending on the severity of CHF, we analyzed the results separately in groups of CHF patients with different functional classes (FC). Thus, among CHF patients with FC I (n = 46), the frequency of the C allele was determined in 47.8% (n = 44), and the T allele in 52.2% (n = 48) cases. Genotypes C / C, C / T, and T / T were detected in 26.1% (n = 12), 43.5% (n = 20), and 30.4% (n = 14) cases, respectively. In the group of CHF patients with FC II (n = 62), the C and T alleles were detected in 48.4% (n = 60) and 51.6% (n = 64) cases, and the C / C, C / T and T / T genotypes were found in 27.4 % (n = 17), 41.9% (n = 26) and 30.6% (n = 19) cases, respectively. And, finally, in the group of CHF patients with FC III (n = 26), the proportions of the frequencies of the C and T alleles were 40.4% (n = 21) and 59.6% (n = 31), and the C / C, C / T and T genotypes / T 19.2% (n = 5), 42.3% (n = 11) and 38.5% (n = 10). The results, according to a comparative assessment, the differences in the frequency of occurrence of alleles and genotypes of polymorphism of the CYP11B2 gene (rs1799998) depending on the functional class of CHF, we can conclude that the functionally unfavorable homozygous T / T genotype of the polymorphic locus rs1799998 of the CYP11B2 gene plays a significant role in the formation of CHF and is a risk factor for the development of a severe course of the disease. In particular, with the carriage of this genotypic variant, the risk of developing FC III in patients with CHF may increase by 2.1 times. The study of the frequency distribution of the NPPB gene (rs198389) in the control group (n = 102) made it possible to establish their occurrence in 59.8% (n = 122) and 40.2% (n = 82) cases. Genotypic frequencies T / T, T / C, and C / C of this polymorphism were detected in 36.3% (n = 37), 47.1% (n = 48), and 16.7% (n = 17) cases, respectively. Along with this, in our studies among the general group of CHF patients (n = 134), the proportion of the T allele decreases to 51.1% (n = 137), and the minor C allele increases to 48.9% (n = 131). In addition to these features, in the genotypic frequencies, the proportion of the T / T genotype decreased to 25.4% (n = 34), while the frequencies American Journal of Medicine and Medical Sciences 2021, 11(9): 611-614 613 of the T / C and C / C genotypes increased to 51.5% (n = 69) and 23.1% (n = 31), respectively. These features may indicate the association of the C / C genotype of the NPPB gene polymorphism (rs198389) with an increased risk of CHF. In addition, it was noted that in the general group of CHF patients, the heterozygosity deficit ranged from 0.51 to 0.5, respectively, and in the control group from 0.47 to 0.48, with D equal to +0.04 and -0.02, which confirms the average level of heterozygosity of the rs198389 locus of the NPPB gene in studied groups. The results of the analysis of the frequency distributions of alleles and genotypes of the rs198389 polymorphism of the NPPB gene in the groups of CHF patients, depending on the FC, had their own differences. The observed allele frequencies in the group of CHF patients with FC I (n = 46) practically did not differ from the initial values in the control group (for the C allele - 59.8% (n = 55) versus 59.8% (n = 44), for the T allele - 40.2% (n = 37) versus 40.2% (n = 82)). At the same time, the proportion of the frequencies of genotypic variants among patients also almost corresponded to those in the control (for the T / T genotype - 37.0% (n = 17) versus 36.3% (n = 37), for the T / C genotype - 45.6% (n = 21) versus 47.1% (n = 48); for the C / C genotype - 17.4% (n = 8) versus 16.7% (n = 17)). However, starting with the group of CHF patients with FC II (n = 62), the frequency of the T allele decreased to 47.6% (n = 59), and the frequency of the C allele increased to 52.4% (n = 65). In accordance with these changes, the share of the T / T genotype decreased to 19.3% (n = 12), and the share of the T / C and C / C genotypes increased to 56.4% (n = 35) and 24.2% (n = 15), respectively. Even more pronounced changes were observed in the group of CHF patients with FC III (n = 26), where the frequencies of the T and C alleles were recorded in 44.2% (n = 23) and 55.8% (n = 29) cases, and the T / T, T genotypes / С and С / С in 19.2% (n = 5), 50.0% (n = 13) and 30.8% (n = 8) cases, respectively. Thus, a decrease in the proportion of carriage of the favorable T allele and the T / T genotype both in the general group of CHF patients and in the groups of CHF patients with FC II and FC III, and, in contrast to this, an increase in the incidence of carriage of the unfavorable C allele and T / C genotypes and С / С, in comparison with their shares in the control group, suggests the presence of their association with the development of severe CHF, to clarify which we evaluated the results of a comparative analysis of the differences in the distribution of allele frequencies and genotypes of the rs198389 polymorphism of the NPPB gene between the examined groups of patients CHF and control. The observed difference in the distribution of the frequency of the unfavorable allele C between the general group of CHF patients and the control group was characterized by its clear increase among patients by 1.4 times (χ2 = 3.5; P = 0.06; OR = 1.4; 95% CI: 0.98-2.06). This was accompanied by a marked decrease in the favorable T / T genotype in the group of CHF patients (χ2 = 3.2; P = 0.07; OR = 0.6; 95% CI: 0.34-1.04) and an increase in the unfavorable T / C genotypes (χ2 = 0.4; P = 0.5; OR = 1.2; 95% CI 0.71-2.0) and С / С (χ2 = 1.5; Р = 0.2; OR = 1.5; 95% CI 0.77-2.90) compared to the same in the control group by 1.2 and 1.5 times, respectively. The reduction in the frequency of occurrence of the homozygous T allele (51.1% versus 59.8%) and the T / T genotype (25.4% versus 36.3%) in the general group of CHF patients compared to the control frequencies directly indicates a decrease in their potentially protective effect on the development of CHF. Meanwhile, the increase in cases of carriage of the homozygous C / C genotype among CHF patients compared to that in the control group by 1.5 times (23.1% versus 16.7%; χ2 = 1.5; P = 0.2; OR = 1.5; 95% CI 0.77-2.90) allows us to assert the presence of the fact of a tendency towards its association with an increased risk of CHF formation. 4. Discussion Expression of the aldosterone synthase gene (CYP11B2) is carried out in the glomerular zone of the adrenal cortex and is mainly regulated by the concentration of sodium and AT II. The CYP11B2 gene is located in the g21 region of chromosome 8 and consists of nine exons and eight introns. Several mutations of the gene have been identified, but the polymorphism of the 5th region of this gene, manifested by the substitution of cytosine for thymine at the 344th position of the nucleotide sequence, has been most fully investigated. According to recent studies, the 344T allele of the CYP11B2 gene is associated with an increase in aldosterone-renin activity in plasma . Prognostic evaluation of HF patients using NP levels is currently recommended by major international guidelines in Europe and the USA . In the STOP-HF Trial also demonstrated that BNP-based screening, along with collaborative care, decreases the risk of new-onset left ventricular dysfunction and HF in subjects at risk of HF. Previous studies have shown the association between the minor C allele of the BNP genetic variant rs198389 and higher circulating levels of BNP in subjects with cardiovascular disease and in general communities including white and black individuals. In vitro studies showed that the rs198389 minor allele is also associated with higher activity in the promoter region of the BNP gene, providing a potential mechanism for the increased plasma levels observed in different cohorts . NT-proBNP measurements may be considered for hospitalized patients with HFrEF upon admission and predischarge, with the baseline NT-proBNP levels measured as soon as possible (at least in the first 24 hours of hospitalization for acute HF patients). A reduction of NT-proBNP levels ≥30% between admission and discharge predicts a better clinical outcome . 614 Nuritdinov Nuriddin Anvarkhodjaevich and Kamilova Umida Kabirovna: Study of the Gene rs1799998 of the CYP11B2 and rs198389 NPPB Polymorphism with Chronic Heart Failure 5. Conclusions Thus, analyzing the results, according to a comparative assessment, the differences in the frequency of occurrence of alleles and genotypes of polymorphism of the CYP11B2 gene (rs1799998) depending on the functional class of CHF, we can conclude that the functionally unfavorable T / T genotype of the polymorphic locus rs1799998 of the CYP11B2 gene plays a significant role in the for-mation of CHF and is a risk factor for the development of a severe course of the disease. The observed difference in the distribution of the NPPB gene (rs198389) frequency of the unfavorable C allele between the group of CHF patients and the control group was characterized by its clear increase among patients by 1.4 times. This was accompanied by a pronounced decrease in the favorable T / T genotype in the group of CHF patients and an increase in the unfavourable T / C and C / C genotypes compared to those in the control group by 1.2 and 1.5 times, respectively.  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