GNB3 C825T Research Articles

Association polymorphism of guanine nucleotide-binding protein β3 subunit (GNB3) C825T and insertion/deletion of the angiotensin-converting enzyme (ACE) gene with peripartum cardiomyopathy.

Peripartum cardiomyopathy (PPCM) is a potentially life-threatening pregnancy-related heart disease. Genetic roles such as gene polymorphisms may relate to the etiology of PPCM. This study analyzes the association between single nucleotide gene polymorphism (SNP) guanine nucleotide-binding protein beta-3 subunit (GNB3) C825T and insertion/deletion (I/D) of the angiotensin-converting enzyme (ACE) gene with the incidence of PPCM. An analytic observational study with a case-control design was conducted at the Integrated Cardiac Service Center of Dr. Soetomo General Hospital, Surabaya, Indonesia. PPCM patients of the case and control groups were enrolled. Baseline characteristic data were collected and blood samples were analyzed for SNP in the GNB3 C825T gene and for I/D in the ACE gene by using the polymerase chain reaction, restriction fragment length polymorphism, and Sanger sequencing. We also assessed ACE levels among different ACE genotypes using a sandwich-ELISA test. A total of 100 patients were included in this study, with 34 PPCM cases and 66 controls. There were significant differences in GNB3 TT and TC genotypes in the case group compared with that in the control group (TT: 35.3% vs. 10.6%, p = 0.003; TC: 41.2% vs. 62.5%, p = 0.022). The TT genotype increased the risk of PPCM by 4.6-fold. There was also a significant difference in the ACE DD genotype in the case group compared with that in the control group (26.5% vs. 9.1%, p = 0.021). DD genotypes increased the risk of PPCM by 3.6-fold. ACE levels were significantly higher in the DD genotype group than in the ID and II genotype groups (4,356.88 ± 232.44 pg/mL vs. 3,980.91 ± 77.79 pg/mL vs. 3,679.94 ± 325.77 pg/mL, p < 0.001). The TT genotype of GNB3 and the DD genotype of the ACE are likely to increase the risk of PPCM. Therefore, these polymorphisms may be predisposing risk factors for PPCM incidence. ACE levels were significantly higher in the DD genotype group, which certainly had clinical implications for the management of PPCM patients in the administration of ACE inhibitors as one of the therapy options.

Polymorphism of genes that characterize the functional state of the vascular wall in newborns born to mothers with preeclampsia

The features of polymorphism of genes characterizing the functional state of the vascular wall in newborns born to mothers with preeclampsia were studied. 150 children were examined, the main group consisted of 100 newborns born to mothers with preeclampsia (PE), the control group included 50 children born to women without preeclampsia. Single-nucleotide polymorphisms were determined in the blood of newborns: ADD1 G1378T (rs4961), AGT T704C (rs699), AGT C521T (rs4762), AGTR1 A1166C (rs5186), AGTR2 G1675A (rs1403543), CYP11B2 –344 C/T (rs1799998), GNB3 C825T (rs5443), NOS3 –786 T/C (rs2070744), NOS3 G894T (rs1799983) using the real-time polymerase chain reaction method with the DTprime 5 device (DNA-Technology, Russia) and the Cardiogenetics kit (DNA-Technology, Russia). The genetic analysis revealed that newborns born to mothers with PE were significantly more likely to have unfavorable genotypes АDD1 1378 G/T, AGT 704 T/C, AGT 704 C/C, AGTR2 1675 A/A, NOS3 (-786) C/C, NOS3 894T/T and alleles АDD1 1378T, AGT 704 C, AGTR2 1675A, NOS3 (-786) C, NOS3 894T. In newborns from mothers without PE, genotypes homozygous for the “wild type” alleles were significantly more common: АDD1 1378 G/G, AGT 704 T/T, CYP11B2 (-344) C/C, NOS3 (-786) T/T, NOS3 894 G/G and the NOS3 (-786) T allele. The revealed changes in newborns born to mothers with PE indicate an increased risk of developing disorders of the cardiovascular system.

The contribution of the AGT, GNB3, MTHFR, MTRR, ApoE, and PPARα polymorphisms to the development of masked arterial hypertension in patients with low and moderate cardiovascular risk

Aim: To assess the probability of masked arterial hypertension (MAH) in patients with low and moderate cardiovascular risk depending on polymorphisms in selected genes.Materials and methods: Ninety two (92) patients (mean age, 41.93±8.92 years) with low and moderate cardiovascular risk without any documented cardiovascular disorders were assessed clinically and had 24-hour ECG monitoring performed, as well as genotyping on the following markers: AGT Thr174Met rs4762, GNB3 C825T rs5443, MTHFR C677T rs1801133, MTRR Ile22Met rs1801394, ApoE Cys130Arg rs 429358, and PPARα G/C rs4253778. Depending on the presence of MAH, the patients were divided into two groups: with newly diagnosed arterial hypertension corresponding to the MAH criteria (n=58, 63%) and with normal office-based and ambulatory blood pressure and normal blood pressure according to the results of 24-hour ECG monitoring (n=34, 37%).Results: Two groups were not different by their age, cardiovascular risk factors, concomitant diseases and clinical characteristics. There were more men than women in the MAH group (р=0.028). In MAH patients, the most prevalent was Ile22Met rs1801394 A/G polymorphism of the MTRR gene (the odds ratio (OR) and relative risk (RR) for MAH were 4.23 [95% сonfidence interval (CI) 1.56–11.72] and 2.17 [1.25–4.12], respectively). The Cys130Arg rs 429358 Т/С genotype polymorphism of the АроЕ gene was also significant. The probability of MAH in the patients with АроЕ Т/С genotype was more than 3-fold higher: OR 3.67 [95% CI 1.34–10.28], RR 2.15 [95% CI 1.17–4.36]. The correlation analysis showed a moderate association between MAH and MTRR and АроЕ gene polymorphisms (Q=0.62 and Q=0.57, respectively).Conclusion: In patients with low and moderate cardiovascular risk, the probability of MAH depends not only from their gender, but also from their genetic background. The candidate genes for MAH in such patients are Ile22Met rs1801394 A/G polymorphism of the MTRR gene and Cys130Arg rs 429358 Т/С polymorphism of the АроЕ gene.

INTERCONNECTION BETWEEN TUBULAR RENAL DYSFUNCTION AND GENES POLYMORPHISM IN PATIENTS WITH ARTERIAL HYPERTENSION

Objective: Objective: to assess the relationship between NGAL concentration as an indicator of tubular disorders, and genetic markers of cardiovascular risk in hypertensive patients. Design and method: Materials and methods: 89 patients of working age with hypertension (mean age 48.32 ± 8.71) were examined, who were divided into 2 groups depending on serum NGAL. Group 1 - 20 patients with NGAL levels above reference values, Group 2 - 69 patients with NGAL levels in the range of normal values. For all patients, to evaluate tubular renal function, the concentration of NGAL in serum was determined by ELISA. All patients were examined for genotypes of AGT Thr174Met, GNB3 C825T, MTHFR C677T, MTRR Ile22Met, ApoE Cys130Arg, PRARA rs4253778. Results: Results: patients in the groups did not significantly differ in age, gender, risk factors, concomitant diseases and therapy, blood pressure and lipid profile. In group 1, the occurrence of AGT, MTHFR, and PRARA gene polymorphism was significantly higher in heterozygous form than in group 2 (p = 0.002, p &lt; 0.001, and p = 0.037, respectively). Patients in the groups did not significantly differ in occurrence of GNB3, MTRR, and ApoE gene polymorphism. Correlation analysis showed a direct relationship between the concentration of NGAL in the blood and the presence of AGT gene polymorphism (r = 0.38; p &lt; 0.05), GNB3 (r = 0.33; p &lt; 0.05), MTHFR (r = 0.35; p &lt; 0.05). The association of NGAL with the polymorphism of the GNB3, MTRR, and ApoE genes was not statistically significant. Conclusions: Conclusions: in patients of working age with hypertension, tubular dysfunction, assessed by the concentration of NGAL in the blood, is associated with the presence of AGT, MTHFR, PRARA gene polymorphism in a heterozygous form.

Meta-analysis of the genetic association between maternal GNB3 C825T polymorphism and risk of pre-eclampsia.

The relationship between the C825T polymorphism of GNB3 (encoding G-protein β3 subunit) and pre-eclampsia risk is unclear. To systematically explore the association between GNB3 C825T and pre-eclampsia. PubMed, EMBASE, Google Scholar, and Chinese National Knowledge Infrastructure (CNKI) databases were searched to September 1, 2020, using keywords including "GNB3 C825T" and "pre-eclampsia". Case-control and cohort studies investigating the relationship between GNB3 C825T polymorphism and pre-eclampsia were included. Two reviewers collected the data independently and calculate odds ratios (ORs) with 95% confidence intervals (CIs). The meta-analysis involved eight studies from seven publications, including 2071 cases and 3419 controls. Overall analysis showed that GNB3 C825T was associated with increased pre-eclampsia risk in the recessive model (OR, 1.21; 95% CI, 1.01-1.44; P=0.04). Subgroup analysis stratified by Hardy-Weinberg equilibrium revealed a relationship between GNB3 C825T and increased risk of pre-eclampsia in the allelic (OR, 1.66; 95% CI, 1.34-2.05; P<0.001), homozygous (OR, 2.12, 95% CI, 1.04-4.32; P =0.04), dominant (OR, 1.91; 95% CI, 1.18-3.11; P=0.009), and recessive (OR, 1.70; 95% CI, 1.03-2.81; P=0.04) models. Maternal GNB3 C825T polymorphism seems to be a risk factor for pre-eclampsia.

The relationship of gene polymorphism with the heart failure risk in patients with hypertension and high adherence to treatment

Aim. To determine the heart failure (HF) risk in patients with hypertension (HTN) and high adherence to treatment, depending on the blood concentration of the N-terminal pro-brain natriuretic peptide (NT-proBNP) and gene polymorphism. Material and methods. The study included 232 patients with HTN without a verified diagnosis of HF. The mean age was 46,13±8,21 years. Patients were evaluated for genotypes by following markers: AGT Thr174Met rs4762, GNB3 C825T rs5443, MTHFR C677T rs1801133, MTRR Ile22Met rs1801394, ApoE Cys130Arg rs 429358, PPAR α G/C rs425377. We also assessed ejection fraction, diastolic function and left ventricular mass index by echocardiography and determined NT-proBNP blood levels. Patients were divided into two groups depending on the NT-proBNP concentration. The group 1 consisted of 64 (27,6%) patients with NT-proBNP >125 pg/ml, the group 2 — 168 (72,4%) patients with NT-proBNP 125 pg/ml, the most significant was the C/T genotype of MTHFR C677T polymorphism (rs1801133), 95% confidence interval (CI) for the odds ratio (OR) and relative risk (RR) of HF was 4,82 and 3,29, respectively (95% CI for OR=2,24-10,60; for OR=1,80-6,39). The A/G and G/G genotypes of the MTRR Ile22Met polymorphism (rs1801394) were statistically significant. The probability of HF with the A/G genotype of the MTRR gene increased by more than 2 times (OR=2,32, 95% CI=1,15-4,64), and the OR of its development was 1,77 (95% CI=1,11-2,69). The probability of HF with the G/G genotype increased more than 3 times (OR=3,65, 95% CI=1,37-9,76), and the OR of its development was 2,20 (95% CI=1,25-3,27). Correlation analysis revealed a direct relationship between the NTproBNP levels and polymorphism of the MTHFR (r=0,47; p 125 pg/ml depends on genetic determinism. Candidate genes for the HF in HTN patients with high adherence to treatment are the genotypes C/T of MTHFR C677T polymorphism (rs1801133), and A/G and G/G of MTRR Ile22Met polymorphism (rs1801394).

P3571Genes polymorphism and renal dysfunction formation in arterial hypertension patients with high adherence to treatment

Abstract Objective To evaluate the contribution of gene polymorphism to the formation of renal dysfunction in patients with hypertension with high adherence to treatment. Methods and materials 88 working-aged subjects with non-complicated arterial hypertension (average age 48,65±7,24 yrs). All patients underwent evaluation of genotype for markers AGT Thr174Met, GNB3 C825T, MTHFR C677T, MTRR Ile22Met. To assess the glomerular function, cystatin C was measured in serum by ELISA, and serum level of NGAL was determined by ELISA to assess the function of the tubules.Depending on genotype peculiarities the following groups were formed: 1) 39 patients who had polymorphism of AGT Thr174Met in homozygous and 49 subjects without one; 2) 62 subjects who had polymorphism of GNB3 C825T in heterozygous and 26 subjects without one; 3) 52 subjects with polymorphism of MTHFR C677T in heterozygous and 36 subjects without one; 4) 48 subjects with polymorphism of MTRR Ile22Met in heterozygous and 40 subjects without one. Results Patients in the groups did not differ in sex, age, risk factors, comorbidities, concomitant medications, BP level, lipid spectrum. In the groups with the presence of the genes GNB3 and MTHFR polymorphism in the heterozygous form, the level of NGAL was significantly higher than in the groups with normal genotypes: 1.67±0.86 ng/ml versus 1.2±0.87 pg/ml (p=0.022), 1.49±0.61 pg/ml versus 1.21±0.56 ng/ml (p=0.034), respectively. At the same time, in these groups, the level of cystatin C was not significantly different. The AGT gene polymorphism groups differed significantly in cystatin C (p&lt;0.001), but did not differ in the level of NGAL. In the group with the presence of the MTRR gene polymorphism, the level of cystatin C and the level of NGAL were significantly higher (p=0.042 and p=0.004, respectively). The correlation analysis revealed a moderate direct interconnections between cystatin C levels and the presence of the AGT gene polymorphism (r=0.46; p=0.017) and MTRR (r=0.33; p=0.039), as well as between the NGAL level and the presence of the GNB3 gene polymorphism (r=0.42; p=0.031), MTHFR (r=0.39; p=0.023) and MTRR (r=0.43; p=0.007). Conclusions In working-aged patients with uncomplicated hypertension with high adherence to treatment, the formation of renal dysfunction with a primary glomerular lesion is associated with the presence of polymorphism of the AGT gene in the heterozygous form. Formation of renal dysfunction with predominant tubular lesion is associated with the presence of GBN3 and MTHFR genes polymorphism of in the heterozygous form. And the formation of renal dysfunction with the damage of both glomeruli and tubules is associated with the presence of the MTRR gene polymorphism of the in the heterozygous form.

CONTRIBUTION OF GENES POLYMORPHISM TO LEFT VENTRICLE HYPERTROPHY IN HIGH COMPLIANCE PATIENTS WITH ARTERIAL HYPERTENSION

Objective: to evaluate the contribution of genes polymorphism to left ventricle hypertrophy (LVH) in high compliance patients with arterial hypertension Design and method: 144 patients with arterial hypertension. The average age was 51,72 ± 5,94 years. Patients were divided into 2 groups depending on presence of LVH been estimated using echocardiography. LVH criterion was LVMMI>115 g/sq.m in male and >95 g/sq.m in female. The 1st group consisted of 65 patients with LVH. The 2nd group included 79 patients without LVH. All the patients were examined for genotypes of the following genes: AGT Thr174Met, GNB3 C825T, MTHFR C677T, MTRR Ile22Met, ApoE Cys130Arg, PPAR G/C. α Results: Patients in the groups were equal in sex, age, comorbidities, BP level, and lipid panel parameters. In the 1st group, the rate of AGT and MTRR heterozygous polymorphism was reliably higher, than in the 2nd one: (p < 0,001 and p = 0,004 respectively). Also, in patients with LVH, both heterozygous and homozygous polymorphism of GNB3 were found more frequently (p = 0,007 and p < 0,001 respectively). There was no significant difference between the groups in MTHFR polymorphism. Correlation analysis showed direct moderate interconnection between LVH and the polymorphism of the following genes: AGT (r = 0,47; p = 0,005), GNB3 (r = 0,48; p = 0,004), MTRR (r = 0,39; p = 0,021). There was no correlation between MTHFR polymorphism and LVH. Conclusions: In high-compliance patients with arterial hypertension appearance of LVH is linearly associated with heterozygous polymorphism of AGT and MTRR genes, and with both heterozygous and homozygous polymorphism of GNB3 gene.

Polimorfismos Genéticos Associados ao Aparecimento de Hipertensão Arterial Numa População Portuguesa

Arterial hypertension is a complex, multifactorial disease, controlled by genetic and environmental factors. Evaluate the genetic susceptibility for developing arterial hypertension and its association with the traditional risk factors in the outbreak of this pathology. Case-control study with 1712 individuals, mean age of 51.0 ± 7.9 years (860 hypertensive patients and 852 controls). Biochemical and traditional risk factors, and genetic variants were evaluated: ACE I/D rs4340, ACE A2350G rs4343, AGT T174M rs4762, AGT M235T rs699 AGTR1 A1166C rs5186, CYP11B2 -344 C/T rs1799998, ADRB1 R389G rs1801253, ADRB2 R16G rs1042713, ADD1 G460W rs4961, SCNN1G G173A rs5718, GNB3 C825T rs5443, ATP2B1 A/G rs2681472, CYP17A1 T/C rs11191548, SLC4A2 C/T rs2303934. The risk of each gene for hypertension was estimated by the dominant, recessive, co-dominant and multiplicative models. By logistic regression, variables associated with hypertension were evaluated. ROC curves were first performed with traditional risk factors and then adding the genetic variants associated with hypertension. Data were analyzed by SPSS for Windows 19.0 and MedCalc v. 13.3.3.0. The genetic variants ADD1 G460W, GNB3 C825T, ACE I/D, ACE A2350G were associated with hypertension. ROC curve with traditional risk factors and these variants showed an increase in the predictive capacity of hypertension (p = 0.018). According to the results of our study, the genetic variants found to be associated with hypertension were: ACE I/D rs4340, ACE A2350G rs4343, ADD1 G460W rs4961 and GNB3 C825T rs5443. The first two variants are associated with hypertension by interfering with the renin-angiotensin-aldosterone system, which plays an important role in regulating blood pressure. It should be noted that genes encoding the components of renin-angiotensin-aldosterone system are natural candidates for the development and progression of hypertension. In our population alpha-aducin polymorphism (ADD1 G460W rs4961) was also associated with hypertension. In a Portuguese population, known to have high salt intake, it makes sense that this polymorphism which is relevant in salt and water management may consequently be relevant in the onset of hypertension. The genetic variant GNB3 C825T rs5443 that affects intracellular signalling was also found to be a strong risk candidate for hypertension. Initially, with the elaboration of the ROC curve and calculation of the AUC using only with traditional risk factors and later by adding the variants ADD1 G460W, GNB3 C825T, ACE I/D and ACE A2350G to the traditional risk factors, we verified that genetic polymorphisms increased the predictive risk of hypertension, when compared to the risk given only by traditional risk factors, with statistical significance (p = 0.018). This suggests that hypertension is a multifactorial disease that results from the interaction of environmental, genetic and lifestyle factors that interact with each other and lead to the advent of this important pathology. In our study, the hypertension-associated polymorphisms are linked to the renin-angiotensin-aldosterone axis (ACE I/D, ACE A2350G), as well as to salt and water management (ADD1 G460W, GNB3 C825T). Through a multivariate analysis, it was concluded that these two last genetic variants together with four of the traditional risk factors (smoking, alcohol consumption, obesity and diabetes) are associated in a significant and independent way with essential hypertension. In a predictive model of hypertension, the introduction of genetic variants slightly increases the predictive value of the model.

Comprehensive insight into functional interaction between GNB3 C825T and eNOS T‐786C, G894T gene polymorphisms and association with susceptibility to diabetic erectile dysfunction

No study has assessed the possible involvementof endothelial nitric oxide synthase (eNOS) T-786C and G894T and G-protein β3 subunit (GNB3) C825T polymorphisms with susceptibility to diabetic vasculogenic erectile dysfunction (VED) in North African subjects. Our aim was to evaluate the interaction and association between these gene polymorphisms and this disorder. A total of 164 type 2 diabetes patients with VED diagnosed with penile color Doppler ultrasonography and 148 age-matched healthy volunteers were genotyped for the rs1799983 (G894T) and rs2070744 (T-786C) of the eNOS gene and the rs5443 (C825T) of the GNB3 gene using the PCR-RFLP method. A significant association of the eNOS G894T (p=0.005) and T-786C (p=0.02) with altered susceptibility to VED was observed. The risk also holds for the G894T and T-786C eNOS gene polymorphisms when excluding patients with dyslipidemia and cardiovascular diseases (p=1.7·10-4 and p=3.2·10-5 , respectively). The univariate odds ratio associated with CC alleles of the eNOS T-786C revealed a four times increased risk for VED (OR=4.04; 95% CI=1.53-10.67;p=0.006). VED risk was also associated with the G894T variant under dominant model (p=0.002) and the T-786C variant under recessive model (p=0.004). Furthermore, the concomitant presence of the combined genotypes of the 894T and 786T strongly affected the predisposition to VED (p=0.007). Our study gave a comprehensive insight into functional interaction between GNB3 and eNOS gene polymorphisms and suggests that the eNOS G894T and T-786C variants are strong predisposing factors of VED susceptibility within men with type 2 diabetes.

Interactions of Genes and Sodium Intake on the Development of Hypertension: A Cohort-Based Case-Control Study.

There have been few studies investigating interactions of G-protein beta3 subunit (GNB3) C825T (rs5443) and dietary sodium intake on the risk of hypertension, i.e., BP salt sensitivity. The study aims to evaluate joint effects of GNB3 polymorphisms and sodium consumption on the development of hypertension. A cohort-based case-control study was conducted in 2014. There are 233 participants with newly diagnosed hypertension in the case group and 699 participants in the gender-matched control group. The primary outcome is the development of hypertension over a 10-year period. The determinants of hypertension were three genotypes of SNP in GNB3 (TT; CT; and CC) and two dietary salt categories on the basis of the level of sodium consumption representing high (>4800 mg/day) and low-sodium (<2400 mg/day) diets. The development of hypertension increased with participants carrying TT genotype and high-sodium diets comparing with those carrying TC or CC genotype with low-sodium diets (adjusted OR 3.23, 95% CI 1.52–6.83) (Rothman synergy index = 3.79). The study suggests that GNB3 C825T polymorphism may influence the response of the renin-angiotensin system to high-sodium diet. It implies that GNB3 can be served as an easy, inexpensive, and early genetic marker of salt sensitivity to blood pressure. Salt-sensitive individuals should pay more attention to salt intake to reduce cardiovascular morbidity or mortality.

IMPACT OF POLYMORPHISM OF CARDIOVASCULAR RISK GENES ON ARTERIAL REMODELLING DEVELOPMENT DEPENDING ON PRESENCE OF SYSTEMIC HYPERTENSION

Aim. To investigate on clinical and genetic characteristics of patients with multiple cardiovascular risk factors depending on the presence or absence of arterial hypertension (AH) and severity of pure arterial stiffness. Material and methods. To the study, 330 patients of economically active age were included, with multiple cardiovascular risk factors at one of Perm city factories. Mean number of the risk factors 5,25±1,04. Mean age 46,67±8,46 y. o. Among the participants 205 (62,12%) males and 125 (37,88%) females. In 177 (53,6) there was AH of grade 1-3 diagnosed. All participants underwent genotype assessment by the markers AGT Thr174Met rs4762, GNB3 C825T rs5443, MTHFR C677T rs1801133, MTRR Ile22Met rs1801394, ApoE Cys130Arg rs 429358, PPARα G/C rs4253778; volume sphygmopletysmography with the CAVI1 measurement. In the first part of the study, patients were selected to 2 groups according to AH presence. In the second part — by CAVI1 level, selected to 3 subgroups: 1st subgroup — no lesion of arteries and CAVI1 9. Results. Among the patients with borderline arteries lesion with AH or with none, the most significant are genotypes С/Т and ТТ of polymorphism Thr174Met rs4762 gene AGT, genotypes С/Т and Т/Т of polymorphism C825T rs5443 gene GNB3, genotypes С/Т and Т/Т of polymorphism C677T rs1801133 gene MTHFR, and genotypes С/С of polymorphism G/C rs4253778 gene PPARα. In patients with the CAVI1 >9 also, regardless of AH presence, were significant the С/Т and ТТ polymorphism Thr174Met rs4762 of gene AGT, genotypes С/Т and Т/Т polymorphism C677T rs1801133 gene MTHFR, genotypes A/G and G/G of polymorphism Ile22Met rs1801394 gene MTRR, and genotype G/С and С/С polymorphism G/C rs4253778 gene PPARα. Presence of AH with no target organ lesion is associated with С/Т polymorphism of the gene GNB3, genotype Т/Т polymorphism of gene MTHFR, and genotypes G/С and С/С of gene polymorphism PPARα. Correlational analysis showed moderate direct correlation of CAVI1 and polymorphism of the genes AGT (r=0,35; p=0,022), GNB3 (r=0,43; p=0,029), MTHFR (r=0,42; p=0,002), MTRR (r=0,43; p=0,025), PPARα (r=0,39; p=0,036). Relation with САVI1 and gene polymorphism АроЕ was not significant. Conclusion. The study witness on the fact that cardiovascular risk shaping and the development of arterial stiffness depend not only on blood pressure level, but patient’s genotype. The data showed that some definite genotypes can be regarded as early markers of cardiovascular risk and arteries lesion in AH patients, and in no AH as well.

Association of G-Protein β3 Subunit C825T Polymorphism with Seasonal Variations in Mood and Behavior.

Objective Seasonal affective disorder and seasonal changes in mood and behavior are associated with several genes that regulate circadian rhythms. In this study, we investigated the relationship between the C825T polymorphism of the G-protein β3 subunit and seasonal variations in mood and behavior in a young healthy Korean population. Methods A total of 507 young Korean participants were recruited through a newspaper advertisement, and their seasonality was evaluated by the Korean version of the Seasonal Pattern Assessment Questionnaire to assess the global seasonality score (GSS). We analyzed the CC, CT, and TT genotypes and their association with the GSS score and subscales. Results T allele carriers of the GNB3 C825T polymorphism were more likely to score higher on body weight and GSS. In the female group, the T allele carriers obtained significantly high total GSS and its subscale scores for mood, body weight, energy level, and appetite; however, differences in genotypes and allele carriers were also observed in the male participants. Conclusion These results suggested that GNB3 C825T polymorphism plays a role in seasonal variations in mood, body weight, energy level, and appetite in a Korean population, particularly in females.

P05.01: Associations of “endothelial dysfunction” genes polymorphism in pregnancy‐induced hypertension among Uzbek women: a case‐control study

Examine genetic polymorphisms associated with the risk of pregnancy-induced hypertension among Uzbek women. A total of 78 cases of pre-eclampsia (PE) patients and 26 healthy pregnant female controls were recruited from the Republican Specialised Scientific and Practical Medical Centre of Ob&Gyn in Uzbekistan. Polymorphisms of 5 genes responsible for «endothelial dysfunction» were examined in this study: endothelial nitric oxide synthase NOS3: -786T>C (rs2070744) and 894 G>T (rs1799983); aldosterone synthase CYP11B2 C-344T (rs1799998); angiotensin II receptor type 1 AGTR1 (rs5186) and guanine-binding protein GNB3 C825T (rs5443). There was disequilibrium on Hardy-Weinberg's test in 2 polymorphism (rs1799983) and rs5443 among estimated 5 polymorphism only in control group. Distribution of allele frequencies of genotypes for polymorphism rs1799983, rs1799998, rs5443 genes in PE and in control group revealed presence of risk and protective markers for this disease. Thus, the relative risk of the G allele and GG genotype polymorphism rs1799983 amounted to 2,55 and 4,34; while T allele of the polymorphism can be regarded as a protective marker in the development of this pathology. There was a significant increase in the frequency of mutant allele T polymorphism rs1799998 gene of aldosterone synthase in PE women compared to controls. Frequencies of allele and genotype polymorphisms of rs2070744, rs5186 and rs5443 statistically have no difference in this study. Comparison of haplotype frequencies of polymorphisms rs2070744 and rs1799983 between patients with PE and the control group showed a risky haplotype TG and the protective haplotype CT. For other haplotypes statistically significant differences were not found. Genetic associations performed in this study may be used as genetic markers of PE susceptibility. It can allow to group risk patients, to work out preventive measures. But, the large studies or meta-analysis are required to confirm these findings.

ПОЛИМОРФИЗМ ГЕНОВ, УЧАСТВУЮЩИХ В РЕГУЛЯЦИИ ФУНКЦИЙ СОСУДОВ, У ЖЕНЩИН С УГРОЖАЮЩИМИ ПРЕЖДЕВРЕМЕННЫМИ РОДАМИ

Введение. Изучение механизмов возникновения угрозы преждевременных родов имеет большую медицинскую и социальную значимость. В настоящее время в условиях демографического кризиса в России остро встает вопрос о предупреждении невынашивания беременности. Это диктует необходимость проведения дальнейших, в том числе и генетических исследований для наиболее эффективной диагностики и прогноза развития данной патологии. Цель исследования. Изучение особенностей полиморфизма генов системы гемостаза у женщин с физиологическим течением беременности и угрожающими преждевременными родами (ПР) в популяции Ивановской области. Материалы и методы. Обследовано 176 беременных в сроки гестации 22–36 недель в популяции Ивановской области: 73 женщины с физиологически протекавшей беременностью и 103 женщины с угрожающими ПР. Изучали особенности полиморфизмов генов (ADD1 G1378T, AGT T704C, AGT C521T, AGTR1 A1166C, AGTR2 G1675A, CYP11B2-344C/T, GNB3 C825T, NOS3 -786 T/C, NOS3 G894T), участвующих в регуляции функций сосудов. Результаты. Полиморфизмы генов, негативно влияющие на состояние сосудистой стенки, широко распространены у женщин в популяции Ивановской области; ряд полиморфизмов достоверно чаще встречается у пациенток с угрожающими ПР. Вероятно, это может быть причастно к нарушению маточно-плацентарного кровообращения и развитию угрожающих ПР. Заключение. Реализация неблагоприятного генетического фона сопряжена с участием определенных факторов внешней среды, комбинация которых индивидуальна. Introduction. Threatened preterm delivery is a great medical and social problem. At present, prevention of miscarriage is very actual question because of demographic crisis in Russia. So for most effective diagnostics and prognosis of this pathology further genetic investigations are needed. The aim: to study polymorphism of hemostasis-associated genes at women with physiological pregnancy and those with threatened preterm delivery among the population of Ivanovo region. Materials and methods. We examined 176 pregnant women at 22–36 weeks of gestation among population of Ivanovo region: 73 women with physiological pregnancy and 103 women with threatened preterm delivery. We studied the peculiarities of genes polymorphisms (ADD1 G1378T, AGT T704C, AGT C521T, AGTR1 A1166C, AGTR2 G1675A, CYP11B2 -344 C/T, GNB3 C825T, NOS3 -786 T/C, NOS3 G894T) involved in regulation of vascular function. Results. Genes polymorphisms adversely aff ecting the vascular wall are common at women in Ivanovo region; some of polymorphisms signifi cantly are more frequent at women with threatened preterm delivery. Probably this can be responsible for disorders of utero-placental blood fl ow and development of threatened preterm delivery. Conclusion. Realization of adverse genetic background might be caused by unfavorable environmental factors, their combination is individual.

Association of G-protein β3 subunit C825T polymorphism with essential hypertension: evidence from 63 729 subjects.

Many studies have reported that G-protein β3 subunit (GNB3) C825T polymorphism is associated with essential hypertension (EH), although this remains subject to debate. Thus, meta-analysis was carried out to clarify this relationship. A total of 75 articles, reporting 81 case-control studies evaluating 28 369 patients and 34 933 control individuals, were assessed. Overall, a significant association was observed in the dominant model (odds ratio (OR)=1.11, 95% CI 1.04-1.19), recessive model (OR=1.09, 95% CI 1.01-1.17), TT vs CC (OR=1.16, 95% CI 1.05-1.28), CT vs CC (OR=1.09, 95% CI 1.02-1.17), and additive model (OR=1.07, 95% CI 1.02-1.13) after pooling all eligible studies. Subgroup analysis by ethnicity and gender demonstrated significantly increased EH only in Caucasians using the dominant (OR=1.22, 95% CI 1.07-1.39; TT vs CC, OR=1.29, 95% CI 1.07-1.54; CT vs CC, OR=1.19, 95% CI 1.05-1.35) and additive (OR=1.16, 95% CI 1.05-1.28) models. In summary, the present meta-analysis indicated the GNB3 C825T polymorphism is related to increased EH exclusively in Caucasians.

Gender Differences in the Alteration of Obesogenic Environments in Korean Children According to GNB3 Polymorphism

Background: A single-nucleotide polymorphism, C825T in the G protein β3 subunit (GNB3) gene, is associated with essential hypertension and obesity. However, the potential interaction of the GNB3C825T polymorphism with obesogenic environmentsin obesity of Korean children has not been closely evaluated yet. Methods: We analyzed data collected from 635 boys and 627 girls aged 8-9 yearsrecruited from seven elementary schools in Seoul, South Korea. Measures of anthropometry and blood pressure (BP) as well as fasting blood samples were used in the analysis. Three-day food records were collected. Results: Obese children had higher BP, lipid profiles and insulinresistance-related factors than did lean children. Higher body mass index (BMI), waist circumference (WC)and BP and lowerplasma lipid profiles were observed in boys than in girls. The genotype frequencies of the GNB3 polymorphism were CC=23.7%, CT=52.1%, and TT=24.2%, and the allele frequencies were C allele=49.7% and T allele=50.3 in the subjects. There was no significant difference according to gender and obesity with allelic frequencies. Boys with the T allele were more obese thanthose with the C allele, but the C and T alleles, according to anthropometrics and plasma variables, did not differ between the obesity and lean groups. In contrast to boys, obese girls with the T allele had lower BMI and WC than those with the C allele, although they had higher plasma cholesteroland energy intakes compared to those with the C allele. We found that the HDL3c subtype, fasting insulin and homeostasis model assessment of insulin resistance decreased with increasing HDL peak amount, which was positively correlated with total HDLcholesterol. However, the HDL subtypes were not changed by the GNB3 C825T polymorphism. Conclusion: The GNB3 C825T polymorphism influences the childhood obesity rate and energy intakesdifferentially by gender in Korean children.

GNB3 C825T Polymorphism and Myocardial Recovery in Peripartum Cardiomyopathy: Results of the Multicenter Investigations of Pregnancy-Associated Cardiomyopathy Study.

Black women are at greater risk for peripartum cardiomyopathy (PPCM). The guanine nucleotide-binding proteins β-3 subunit (GNB3) has a polymorphism C825T. The GNB3 TT genotype more prevalent in blacks is associated with poorer outcomes. We evaluated GNB3 genotype and myocardial recovery in PPCM. A total of 97 women with PPCM were enrolled and genotyped for the GNB3 T/C polymorphism. Left ventricular ejection fraction (LVEF) was assessed by echocardiography at entry, 6 and 12 months postpartum. LVEF over time in subjects with the GNB3 TT genotype was compared with those with the C allele overall and in black and white subsets. The cohort was 30% black, age 30+6, LVEF 0.34+0.10 at entry 31+25 days postpartum. The % GNB3 genotype for TT/CT/CC=23/41/36 and differed markedly by race (blacks=52/38/10 versus whites=10/44/46, P<0.001). In subjects with the TT genotype, LVEF at entry was lower (TT=0.31+0.09; CT+CC=0.35+0.09, P=0.054) and this difference increased at 6 (TT=0.45+0.15; CT+CC=0.53+0.08, P=0.002) and 12 months (TT=0.45+0.15; CT+CC=0.56+0.07, P<0.001.). The difference in LVEF at 12 months by genotype was most pronounced in blacks (12 months LVEF for GNB3 TT=0.39+0.16; versus CT+CC=0.53+0.09, P=0.02) but evident in whites (TT=0.50++0.11; CT+CC=0.56+0.06, P=0.04). The GNB3 TT genotype was associated with lower LVEF at 6 and 12 months in women with PPCM, and this was particularly evident in blacks. Racial differences in the prevalence and impact of GNB3 TT may contribute to poorer outcomes in black women with PPCM.

Zinc Finger 259 Gene Polymorphism rs964184 is Associated with Serum Triglyceride Levels and Metabolic Syndrome.

Metabolic syndrome (MetS) is characterized by a cluster of cardiovascular risk factors that include: abdominal obesity, dyslipidaemia, hypertension, insulin resistance and impaired glucose tolerance. Recent genome wide association studies have identified several susceptibility regions involved in lipid metabolism that are also associated with MetS. We have explored the association of 9 genetic polymorphisms involved in lipid metabolism and hypertension, including: MTHFR C677T, SELE L554F, FGB - 455G>A, GNB3 C825T, ZNF259 C>G, PSRC-1 A>G, CETP I405V, LPL S447X and LPA C>T in 97 subjects with MetS and 96 individuals without MetS who were recruited randomly from Mashhad stroke and heart atherosclerotic disorder (MASHAD) study using a stratified cluster random sampling technique. Anthropometric parameters and biochemical measurements were determined in all the subjects. Genotyping was carried out followed by univariate and multivariate analyses. The subjects with MetS had a higher triglyceride and lower HDL- C. CG+ GG genotypes of ZNF259 polymorphism (rs964184 C>G) and TT+CT genotypes of MTHFR C677T (rs1801133) were associated with MetS, and individuals carrying the G allele for ZNF259 or the T allele for MTHFR polymorphisms were associated with MetS (e.g, odds ratio (OR) for CG+GG genotypes vs. CC wild type: 2.52, CI=1.33-4.77; P=0.005). However, after multiple comparison adjustment, this relationship remained significant only for CG+ GG genotypes of ZNF259 polymorphism. Moreover, the ZNF259 CG+ GG genotypes were associated with increased serum concentrations of triglycerides and LDL-C, compared to the wild type. These data support the necessity for further studies in larger multicenter settings.

Synergistic Effects of ACE Insertion/Deletion and GNB3 C825T Polymorphisms on the Efficacy of PDE-5 Inhibitor in Patients with Pulmonary Hypertension

Background: The insertion/deletion (I/D) polymorphism in the angiotensin-converting enzyme gene (ACE) and the C825T polymorphism in the G-protein β3 subunit gene (GNB3) are associated with the efficacy of phosphodiesterase-5 inhibitor (PDE-5I) in erectile dysfunction. In addition, GNB3 genotypes could be associated with clinical worsening in pulmonary hypertension (PH) treated with PDE-5I. However, no studies have described the synergistic effects of gene polymorphisms on drug efficacy in patients with PH. Objectives: We aimed to examine the effects of combined ACE/GNB3 polymorphisms on the efficacy of PDE-5I in patients with PH. Methods: This was a retrospective uncontrolled study. Ninety patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic PH (CTEPH) were treated with PDE-5I. Freedom from clinical worsening and pre- and post-treatment parameters, including the 6-min walk distance (6MWD) and serum brain natriuretic peptide (BNP) levels, were compared between patients with ACE/GNB3 II/TT and non-II/TT genotypes. Results: Time to clinical worsening was significantly longer in patients with the II/TT genotype than in those with the non-II/TT genotype (5-year freedom from clinical worsening: 100 vs. 48.8%, respectively; p = 0.018), even in patients with CTEPH alone. Post-treatment 6MWD and BNP levels in patients with the II/TT genotype tended to be better than those in patients with the non-II/TT genotype. The ACE/GNB3 genotype was a significant predictor of clinical worsening, even after adjusting for pulmonary vascular resistance and 6MWD. Conclusions:ACE and GNB3 polymorphisms may synergistically influence the efficacy of PDE-5I in patients with PH.