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Relationship between rs198389 NPPB gene polymorphism and chronic heart failure

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https://www.eduzhai.net American Journal of Medicine and Medical Sciences 2021, 11(8): 553-556 DOI: 10.5923/j.ajmms.20211108.01 Association of rs198389 NPPB Gene Polymorphism with Chronic Heart Failure Zakirova Gulnoza Alisherovna1, 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 rs198389 NPPB gene in patients with chronic heart failure (CHF). In patients with CHF 152 Uzbek nationality have been studied the alleles and genotypes rs198389 NPPB gene. The observed difference in the distribution of the frequency of the unfavorable C allele between the general 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 unfavorable T / C and C / C genotypes compared to those in the control group by 1.2 and 1.5 times, respectively. Keywords Chronic heart failure, B-type natriuretic peptide, Gene polymorphism 1. Introduction According to numerous studies, it became obvious that the effect of environmental factorsis realized in connection with the genotype of the individual features. The problem is that not previously manifested in other living conditions of the particular genotype in the changed social conditions “implemented” its potential pathogenetic significance, become individual genetic risk factors, so the study of genetics of cardiovascular disease becomes more theoretical and practical significance [1]. 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 [2]. 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 [3]. However, molecular genetic testing can detect features of etiopathogenesis and course the most common cardiovascular disease in each patient. 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 * Corresponding author: umida_kamilova@mail.ru (Kamilova Umida Kabirovna) Received: Jul. 26, 2021; Accepted: Aug. 5, 2021; Published: Aug. 7, 2021 Published online at https://www.eduzhai.net 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) [4,5]. Natriuretic peptide (NP), including B-type natriuretic peptide (BNP) and N-terminal 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) [6]. HF is a chronic disabling disease affecting approximately 26 million people globally. HF presents a high economic burden with lengthy and repeated hospitalizations accounting for the majority of healthcare expenditure. BNP release is regulated at the level of gene expression, and synthesized in bursts as prepro-BNP, which is processed intracellularly to pro-BNP1-108, then cleaved and secreted as a biologically inactive N-terminal fragment N-BNP1-76 (designated NT-proBNP) (plasma halflife ~70 minutes) and the biologically active, 32-amino-acid ring structure BNP77-108 (plasma half-life 22 minutes) [7]. 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 [8]. The aim of our study was to evaluate the role of polymorphism rs198389 NPPB gene 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 rs198389 NPPB gene. The control group consisted of 75 554 Zakirova Gulnoza Alisherovna and Kamilova Umida Kabirovna: Association of rs198389 NPPB Gene Polymorphism with Chronic Heart Failure 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 rs198389 NPPB gene 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 T and C alleles of the polymorphic variant 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 (Table 1). Table 1. Expected and observed frequencies of distribution of alleles and genotypes of NPPB gene polymorphism (rs 198389) in the group of patients with CHF Alleles Т С Genotype Т/Т T/С С/С Total Allele frequency 0.51 0.49 Genotype frequency Observed Ho Expected He χ2 p df 0.25 0.26 0,03 0.51 0.5 0.06 0.7 1 0.24 0.24 0.03 1.0 1.0 0.1 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 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 American Journal of Medicine and Medical Sciences 2021, 11(8): 553-556 555 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. 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 [12]. 5. Conclusions The observed difference in the distribution of the frequency of the unfavorable C allele between the general 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 unfavorable T / C and C / C genotypes compared to those in the control group by 1.2 and 1.5 times, respectively. 4. Discussion Prognostic evaluation of HF patients using NP levels is currently recommended by major international guidelines in Europe and the USA [9,10]. The 2017 American College of Cardiology (ACC)/American Heart Association (AHA) HF guideline recommends to measure BNP or NT-proBNP levels for establishing prognosis or disease severity in chronic HF.27 However, there is a lack of consensus on how prognostic information from NT-proBNP can be applied to patient management. During the meeting, the panel reviewed the current literature on the prognostic value of NT-proBNP. Based on the scientific evidence and clinical experience of the panel, recommendations were proposed and discussed until agreed upon by all of the panel members. Prognostic cutoffs are recommended acknowledging that prognostic risk is likely to be linear rather than dichotomous. 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. More importantly, these data demonstrated that, in clinical practice, NT-proBNP values can be used as a tool to help overcome physician inertia and enhance up-titration of HF medications in stable HF patients, especially for those who are treated in the outpatient setting [11]. 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 REFERENCES [1] Nielsen JB, Rom O, Surakka I, Graham SE, Zhou W, Roychowdhury T. et al. Loss-of-function genomic variants highlight potential therapeutic targets for cardiovascular disease. Nat Commun. 2020 Dec 18; 11(1): 6417. [2] Glicksberg BS, Amadori L, Akers NK. et al. Integrative analysis of loss-of-function variants in clinical and genomic data reveals novel genes associated with cardiovascular traits. BMC Med Genomics. 2019 Jul 25; 12(Suppl 6): 108. doi: 10.1186/s12920-019-0542-3. Erratum in: BMC Med Genomics. 2019 Nov 5; 12(1): 154. [3] Seidelmann SB, Vardeny O, Claggett B, al. An NPPB Promoter Polymorphism Associated With Elevated N-Terminal pro-B-Type Natriuretic Peptide and Lower Blood Pressure, Hypertension, and Mortality. 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JACC Basic Transl Sci. 2021 Jun 16; 6(6): 497-504. Copyright © 2021 The Author(s). Published by Scientific & Academic Publishing This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/

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