Association of the Single Nucleotide Polymorphisms in the Renin-Angiotensin-Aldosterone System with Hypertension in the Uzbek Population.

OBJECTIVE: This research aims to identify the association between the nine polymorphic variants (rs4961, rs699, rs4762, rs5186, rs1403543, rs1799998, rs5443, rs2070744, rs1799983) and the occurrence of hypertension and its clinical manifestations in the Uzbek population. METHODS: The study included 227 individuals, comprising 179 patients with hypertension and 48 controls. Clinical parameters such as age, weight, blood glucose, triglycerides, total cholesterol, low-density lipoprotein and high-density lipoprotein, blood urea nitrogen, creatinine, pulse wave velocity, left ventricular mass, and microalbuminuria levels were identified. We assessed the distribution of allele frequencies of these polymorphic variants in the Uzbek population to establish their association with cardiovascular diseases and their clinical manifestations. RESULTS: Genetic analysis of the polymorphic variants demonstrated a significant association of the AGT 521 C>T variant with arterial hypertension [P ≤ 0.01; Odds Ratio (OR) = 2.91]. The NOS3 -786 T>C variant correlated with left ventricular hypertrophy (P ≤ 0.05; OR = 0.35) and increased pulse wave velocity (P ≤ 0.01; OR = 0.21). The correlations of the AGTR2 1675 G>A variant with left ventricular hypertrophy (P ≤ 0.01; OR = 1.59) and increased pulse wave velocity (P ≤ 0.01; OR = 0.33) were identified. The AGT 704 T>C variant showed a significant association with increased pulse wave velocity (P ≤ 0.05; OR = 2.73). CONCLUSION: Four of the nine studied polymorphic variants were associated with clinical manifestations of hypertension in the Uzbek population. These variants can be used as genetic biomarkers to identify the risks of developing cardiovascular diseases and hypertension in the Uzbek population.

E670G PCSK9 polymorphism in HeFH & CAD with diabetes: is the bridge to personalized therapy within reach?

Objective: To assess the distribution of PCSK9 E670G genetic polymorphism and PCSK9 levels in patients with Coronary Artery Disease (CAD) and Heterozygous Familial Hypercholesterolemia (HeFH), based on the presence of type 2 Diabetes Mellitus (T2DM). Methods: The study included 201 patients with chronic CAD, including those with HeFH (n=57, group I) and without it (n=144, group II). DLCN was used to diagnose HeFH. The PCSK9 E670G (rs505151) polymorphism was genetically typed using the PCR-RFLP procedure. In both the patient and control groups, the genotype frequency matched the Hardy-Weinberg equilibrium distribution (P>0.05). Results: There were twice more G alleles in group I (13, 11.4%) than in group II (17, 6.0%), and thrice more (1, 3.0%) than in the healthy control group; nevertheless, these differences weren't statistically significant. Simultaneously, PCSK9 levels were higher in HeFH patients (P<0.05) compared to non-HeFH patients not taking statins (n=63). T2DM was equally represented in groups I and II (31.6% vs. 33.3%). But carriers of AG+GG genotypes in group I had a higher chance of having a history of T2DM (RR 4.18; 95%CI 2.19-8.0; P<0.001), myocardial infarction (RR 1.79; 95%CI 1.18-2.73; P<0.05), and revascularization (RR 12.6; 95%CI 4.06-38.8; P<0.01), than AA carriers. T2DM was also more common among G allele carriers (RR 1.85; 95% CI 1.11-3.06; P<0.05) in patients with non-HeFH. Conclusion: T2DM in patients with CAD, both with HeFH and non-HeFH, in the Uzbek population was significantly more often associated with the presence of the "gain-of-function" G allele of the PCSK9 E670G genetic polymorphism.

Genome sequence diversity of SARS-CoV-2 obtained from clinical samples in Uzbekistan.

Tracking temporal and spatial genomic changes and evolution of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are among the most urgent research topics worldwide, which help to elucidate the coronavirus disease 2019 (COVID-19) pathogenesis and the effect of deleterious variants. Our current study concentrates genetic diversity of SARS-CoV-2 variants in Uzbekistan and their associations with COVID-19 severity. Thirty-nine whole genome sequences (WGS) of SARS-CoV-2 isolated from PCR-positive patients from Tashkent, Uzbekistan for the period of July-August 2021, were generated and further subjected to further genomic analysis. Genome-wide annotations of clinical isolates from our study have revealed a total of 223 nucleotide-level variations including SNPs and 34 deletions at different positions throughout the entire genome of SARS-CoV-2. These changes included two novel mutations at the Nonstructural protein (Nsp) 13: A85P and Nsp12: Y479N, which were unreported previously. There were two groups of co-occurred substitution patterns: the missense mutations in the Spike (S): D614G, Open Reading Frame (ORF) 1b: P314L, Nsp3: F924, 5`UTR:C241T; Nsp3:P2046L and Nsp3:P2287S, and the synonymous mutations in the Nsp4:D2907 (C8986T), Nsp6:T3646A and Nsp14:A1918V regions, respectively. The "Nextstrain" clustered the largest number of SARS-CoV-2 strains into the Delta clade (n = 32; 82%), followed by two Alpha-originated (n = 4; 10,3%) and 20A (n = 3; 7,7%) clades. Geographically the Delta clade sample sequences were grouped into several clusters with the SARS-CoV genotypes from Russia, Denmark, USA, Egypt and Bangladesh. Phylogenetically, the Delta isolates in our study belong to the two main subclades 21A (56%) and 21J (44%). We found that females were more affected by 21A, whereas males by 21J variant (χ2 = 4.57; p ≤ 0.05, n = 32). The amino acid substitution ORF7a:P45L in the Delta isolates found to be significantly associated with disease severity. In conclusion, this study evidenced that Identified novel substitutions Nsp13: A85P and Nsp12: Y479N, have a destabilizing effect, while missense substitution ORF7a: P45L significantly associated with disease severity.

Interrelation between the rs2200733 polymorphism of the ATFB5 gene and atrial fibrillation in Uzbek patients.

OBJECTIVE: Atrial fibrillation (AF) is one of the most common cardiac arrhythmias and a major predictor of morbidity and mortality. AF is a polygenic and polyetiological disease. In various ethnic groups, the strongest and most independent relationship with the development of AF was found with the 4q25 locus, where the ATFB5 gene is located. An analysis of the literature data showed that the carriage of the TT genotype of the rs2200733 ATFB5 gene polymorphism is the most unfavorable genotype for the development of AF. The purpose of the study was to identify the prevalence of genotypes and alleles of the rs2200733 polymorphism of the ATFB5 gene in Uzbek patients with AF. METHODS: The study included 69 Uzbek patients with paroxysmal (n=20) and persistent AF (n=49). The control group (n=30) was composed of Uzbek patients without AF. Genotyping for the carriage of allelic variants of the rs2200733 polymorphism of the ATFB5 gene was performed using the Polymerase Chain Reaction-Restriction Length Polymorphism (PCR-RFLP) method. The distribution of the C and T alleles and the CC, CT, and TT genotypes of the rs2200733 polymorphism of the ATFB5 gene in patients with AF and controls were compared. RESULTS: After genotyping 69 patients with AF, the following distribution of the ATFB5 gene polymorphism rs2200733 was revealed: the CC genotype was detected in 35 (50.72%) patients, the CT genotype in 25 (36.23%) patients, and the TT genotype in 9 (13.05%) patients (p<0.001, χ²=22.435). Moreover, the C allele was detected in 95 (68.8%) patients, and the T allele was detected in 43 (31.2%) patients (p<0.001, χ²=37.696). The distribution of genotypes in the control group was as follows: the CC genotype was detected in 17 individuals (56.7%), the CT genotype was detected in 12 individuals (40%), and the TT genotype was detected in 1 individual (3.3%) (p<0.001, χ²=20.100). Moreover, the C allele was detected in 46 (76.7%) patients, and the T allele was detected in 14 (23.3%) patients (p<0.001, χ²=32.033). The TT genotype of the ATFB5 gene was found to be significantly more prevalent in patients with AF than in controls (13.1% vs 3.3%, p=0.0001). CONCLUSION: The TT genotype of the rs2200733 polymorphism of the ATFB5 gene was found to be significantly more prevalent in Uzbek patients with AF than in controls.

Personalized rosuvastatin therapy in problem patients with partial statin intolerance.

INTRODUCTION: The aim was to study the pharmacogenetic determinants of switching simvastatin-intolerant ethnic Uzbek patients with coronary artery disease (CAD) to rosuvastatin treatment. MATERIAL AND METHODS: The study included 50 patients with CAD, who demonstrated statin-induced adverse liver symptoms, accompanied by an elevation in transaminase level (3-fold or more in 37 cases) or statin-induced adverse muscle symptoms, accompanied by elevations in serum (CK > 3 times above the upper limit of normal (ULN)) in simvastatin treatment with a dose of 10-20 mg/day. The control group consisted of 50 patients without side effects. Patients were genotyped for polymorphisms in the genes coding for the cytochrome P450 (CYP) metabolic enzymes CYP3A5(6986A>G), CYP2C9(430C>T), CYP2C9(1075A>C), and hepatic influx and efflux transporters SLCO1B1(521T>C) and BCRP(ABCG2, 421C>A) by means of the PCR-RFLP method. RESULTS: When the 50 patients of the case group were switched to the starting rosuvastatin dose of 5 mg, intolerance symptoms were not observed in 29 (58%) versus 21 with adverse symptoms. In this case-control study, the groups differed significantly only in the prevalence of the *3/*3 genotype CYP3A5 (OR = 5.25; 95% CI: 1.6-17.8; p = 0.014). CONCLUSIONS: In a considerable proportion of ethnic Uzbek patients with CAD and simvastatin intolerance symptoms, serious side effects when switching to a starting dose of rosuvastatin were not observed, and it should be noted that in most cases (72.4%) this phenomenon was observed among the carriers of *3/*3 genotype of the CYP3A5 (6986A> G) gene.

Genetic diversity, linkage disequilibrium, and association mapping analyses of Gossypium barbadense L. germplasm.

Limited polymorphism and narrow genetic base, due to genetic bottleneck through historic domestication, highlight a need for comprehensive characterization and utilization of existing genetic diversity in cotton germplasm collections. In this study, 288 worldwide Gossypium barbadense L. cotton germplasm accessions were evaluated in two diverse environments (Uzbekistan and USA). These accessions were assessed for genetic diversity, population structure, linkage disequilibrium (LD), and LD-based association mapping (AM) of fiber quality traits using 108 genome-wide simple sequence repeat (SSR) markers. Analyses revealed structured population characteristics and a high level of intra-variability (67.2%) and moderate interpopulation differentiation (32.8%). Eight percent and 4.3% of markers revealed LD in the genome of the G. barbadense at critical values of r2 ≥ 0.1 and r2 ≥ 0.2, respectively. The LD decay was on average 24.8 cM at the threshold of r2 ≥ 0.05. LD retained on average distance of 3.36 cM at the threshold of r2 ≥ 0.1. Based on the phenotypic evaluations in the two diverse environments, 100 marker loci revealed a strong association with major fiber quality traits using mixed linear model (MLM) based association mapping approach. Fourteen marker loci were found to be consistent with previously identified quantitative trait loci (QTLs), and 86 were found to be new unreported marker loci. Our results provide insights into the breeding history and genetic relationship of G. barbadense germplasm and should be helpful for the improvement of cotton cultivars using molecular breeding and omics-based technologies.

Analyses of Fusarium wilt race 3 resistance in Upland cotton (Gossypium hirsutum L.).

Fusarium wilt [Fusarium oxysporum f.sp. vasinfectum (FOV) Atk. Sny & Hans] represents a serious threat to cotton (Gossypium spp.) production. For the last few decades, the FOV pathogen has become a significant problem in Uzbekistan causing severe wilt disease and yield losses of G. hirsutum L. cultivars. We present the first genetic analyses of FOV race 3 resistance on Uzbek Cotton Germplasm with a series of field and greenhouse artificial inoculation-evaluations and inheritance studies. The field experiments were conducted in two different sites: the experimental station in Zangiota region-Environment (Env) 1 and the Institute of Cotton Breeding (Env-2, Tashkent province). The Env-1 was known to be free of FOV while the Env-2 was known to be a heavily FOV infested soil. In both (Env-1 and Env-2) of these sites, field soil was inoculated with FOV race 3. F2 and an F3 Upland populations ("Mebane B1" × "11970") were observed with a large phenotypic variance for plant survival and FOV disease severity within populations and among control or check Upland accessions. Wilt symptoms among studied F2 individuals and F3 families significantly differed depending on test type and evaluation site. Distribution of Mendelian rations of susceptible (S) and resistant (R) phenotypes were 1S:1R field Env-1 and 3S:1R field Env-2 in the F2 population, and 1S:3R greenhouse site in the F3 population. The different segregation distribution of the Uzbek populations may be explained by differences in FOV inoculum level and environmental conditions during assays. However, genetic analysis indicated a recessive single gene action under high inoculum levels or disease pressure for FOV race 3 resistance. Uzbek germplasm may be more susceptible than expected to FOV race 3, and sources of resistance to FOV may be limited under the FOV inoculum levels present in highly-infested fields making the breeding process more complex.

Two tobacco proline dehydrogenases are differentially regulated and play a role in early plant development.

Proline dehydrogenase is the rate-limiting enzyme in proline degradation and serves important functions in the stress responses and development of plants. We isolated two tobacco proline dehydrogenases, NtPDH1 and NtPDH2, in the course of screening for genes upregulated in stressed tobacco (Nicotiana tabacum) microspores. Expression analysis revealed that the two genes are differentially regulated. Under unstressed conditions, their steady-state transcript levels were similar in mature pollen and apical meristems, whereas NtPDH2 was expressed predominantly in vegetative organs, styles, and ovules. The expression of NtPDH1 was maintained at a constant low level during 24 h of dehydration, whereas NtPDH2 was upregulated within 1 h after the onset of stress and subsequently downregulated to undetectable levels. Differential and sustained expression was also found for the two enzymatic isoforms of Arabidopsis thaliana AtPDH. Silencing of the NtPDH genes by RNA interference using the CaMV 35S promoter led to increased proline contents, decreased seed set, delayed seed germination and retarded seedling development pointing towards an important function of at least one of the two NtPDH genes during plant reproductive development.