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.

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.

Burden of familial heterozygous hypercholesterolemia in Uzbekistan: Time is muscle.

BACKGROUND AND AIMS: We aimed to assess the disease burden and to study the molecular genetic characteristics of heterozygous familial hypercholesterolemia (HeFH) patients within the Uzbek population to develop a program of early disease detection and effective treatment measures. METHODS: 201 patients were included in the study, of whom 57 with chronic stable coronary artery disease (SCAD) and HeFH, and 144 with SCAD without HeFH belonging to the control group, and divided into two subgroups: A, statin free before the study (n = 63) and B (n = 81), who took statin outpatiently. We applied the Dutch Lipid Clinic Network Criteria (DLCN) to diagnose HeFH. Serum level of PCSK-9 was measured with the ELISA Kit. The genetic typing at PCSK9 E670G (rs505151) polymorphism was performed with the PCR-RFLP method. RESULTS: Underestimation of early lipid studies and inadequate treatment in HeHF patients within the Uzbek population are accompanied by a 1.8-time increase of more frequent history of myocardial infarction (p < 0.05), a 3-time stroke (p < 0.05) and 2-time percutaneous coronary intervention (p < 0.05). The study of genotypes and alleles of PCSK9 E670G (rs505151) polymorphism allowed to state that сarriage of the «damaging ¼â€¯allele G in SCAD and HeHF patients was 2 times higher (11.4%), than in non HeHF (6.0%) and 3 times (3.0%) than in healthy ones, but the differences were not significant. Herewith, G-carriership is accompanied by a higher incidence of myocardial infarction (p < 0.05) and stroke (p < 0.05), coronary artery bypass grafting in anamnesis (p < 0.001), and number of plaques in carotids (p < 0.05). In group I of SCAD patients with HeFH, 18 (31.6%) cases of diabetes mellitus were observed, which did not exceed their number in group II (48, 33.3%). However, most of them were carriers of the G allele (82.0%, p < 0.001). Despite treatment with rosuvastatin 20-40 mg/day, in HeHF patients after 3 months, the level of total cholesterol (p < 0.001) and LDL-C (p < 0.001) was significantly higher than in the control group. CONCLUSIONS: Improvement of early diagnosis of FH, including genetic confirmation, and preventional high-intensity statin therapy or a combination of statins with ezetimibe to achieve the target level of LDL-C, is the closest tactical objective for prevention of MACE within the Uzbek population.

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.

Simvastatin intolerance genetic determinants: some features in ethnic Uzbek patients with coronary artery disease.

INTRODUCTION: The objective is to study the influence of CYP3A5 (6986A>G), CYP2C9 (430C>T), CYP2C9 (1075A>C), SLCO1B1 (521T>C) and BCRP (ABCG2, 421C>A) gene polymorphisms on the development of simvastatin intolerance in ethnic Uzbek patients with coronary artery disease (CAD). MATERIAL AND METHODS: The case group contained 50 patients with clinical simvastatin-induced intolerance symptoms; the control group contained 50 patients without side-effects. Genotyping was performed by means of the PCR-RFLP method. RESULTS: Among 37 patients with simvastatin-induced liver symptoms the *3/*3 genotype of the CYP3A5 gene (p = 0.0001) and variant genotype of the CA BCRP gene were observed more frequently than in the control group (p = 0.0001). However, when the 13 patients who had statin-associated muscle symptoms (SAMS) were compared with the control group (n = 50), it was found that in the case group the 3*/3* genotype of the CYP3A5 gene (OR = 8.6; 95% CI: 2.1-34.1; p = 0.003) and C allele carriers of the gene polymorphism SLCO1B1 (OR = 3.54; 95% CI: 1.35-9.27; Χ2 = 5.7; p = 0.017) were predominant. CONCLUSIONS: The *3/*3 genotype of the CYP3A5 (6986A>G) gene and CA genotype of the BCRP (ABCG2, 421C>A) gene were associated with simvastatin-induced liver symptoms in ethnic Uzbek CAD patients, whereas in patients with simvastatin-associated muscle symptoms (SAMS), the combination of *3/*3 genotype of CYP3A5 (6986A> G) and carriage of the C allele of the SLCO1B1 gene polymorphism was predominant.

C825T polymorphism of the G-protein ß3 subunit and its association with essential hypertension in Uzbek males.

OBJECTIVES: We investigated the association between the C825T polymorphism of the G-protein ß3 subunit (GNB3) gene with essential hypertension (EH) and cardiovascular remodeling markers in Uzbek males. STUDY DESIGN: The study included 174 Uzbek men (mean age 49±10 years) with untreated EH of stage 1-2 and 60 normotensive males. The C825T polymorphism of the GNB3 gene in the patient and control groups was determined by polymerase chain reaction. The patients were assessed with blood pressure measurements, ambulatory blood pressure monitoring, body mass index (BMI), carotid artery intima-media thickness (IMT), flow-mediated dilation (FMD) of the brachial artery, echocardiography, and urinary albumin excretion (UAE) level. RESULTS: The frequencies of the CC, CT, and TT genotypes were 36.8%, 53.5%, and 9.8% in hypertensive men, and 0%, 83.3%, and 16.7% in healthy men, respectively (p=0.0001). The frequencies of the C and T alleles were 63.8% and 36.2% in the hypertensive group, and 41.7% and 58.3% in the control group, respectively (p=0.0001). The CC genotype exhibited a significantly greater risk for hypertension compared to CT and TT genotypes (OR=72.38, 95% CI 4.40-1190.34). The C825 allele showed a higher association with hypertension in comparison to the 825T allele (OR 2.41, 95% CI 1.58-3.68). Compared to patients with the CT+TT genotypes, the CC genotype carriers had significantly higher BMI (p=0.0001), systolic (p=0.0001) and diastolic (p=0.003) blood pressures (SBP/DBP), higher nighttime DBP (p=0.042), a greater nighttime variability in both SBP and DBP (p=0.002), and greater carotid artery IMT (p=0.0001) and UAE (p=0.015) values. CONCLUSION: Our findings show a significant association between the GNB3/C825T gene polymorphism and EH, with the CC genotype exhibiting higher blood pressure, BMI, and vascular remodeling markers in Uzbek hypertensive men.