AGT Genotypes Research Articles

THE ROLE OF GENES COMBINATION IN ESSENTIAL ARTERIAL HYPERTENSION

Abstract Objective: The aim of the study was to analyze the association of AGT (T704C) and VDR (1056T/C) genes polymorphisms combination with essential hypertension (EH). Design and method: The study involved 100 patients suffering from PAH with target-organ damaging, moderate, high or very high cardiovascular risk. Among them there were 79.0% (79) women and 21.0% (21) men, average age 59.87 ± 8.02 yo. The control group involved 30 practically healthy persons, matched by age (43.36 ± 7.1 y) and gender (62.5% women, 37.5% men). All enrolled / screened patients signed the Informed Consent to participate in the research. The genes polymorphism AGT (704 T > C) and VDR (1056T/C) was studied with PCR based method. Results: The genotypes distribution of the AGT (704T > C) and VDR (1056T/C) genes genotypes in patients vs control group did not differ reliably and was as follows: for AGT gene TT-, TC- and CC –genotypes - 13.89% vs 16.67%, 59.72% vs 54.17% and CC-genotype - 26.39% vs 29.17%; for VDR gene AA-, AG-, GG-genotypes – 23.0% vs 30.0%, 50.0% vs 46.67%, 27.0% vs 23.33% (p > 0.05) accordingly. Distribution of polymorphic variants of both genes corresponded to the Hardy-Weinberg Equilibrium (p > 0.05). The distribution of mutant genotypes combinations of both genes in study and control groups was as follows: TC + AG - 31.94% vs 29.17% (p > 0.05), TC + GG – 16.67% vs 8.33% (p > 0.05), TT + AG – 8.33% vs 4.17% (p > 0.05), TT + GG – 4.17% vs 8.33% (p > 0.05). The polymorphic variant combinations of both genes don’t influence the risk of EH in observed population. However, in AA-genotypes carrier of VDR gene hypertensive women increased a risk of EH almost 3 times [OR = 3.08; 95% CI: 1.02–10.25; p = 0.047]. Conclusions: Thus, the mutant genotypes combinations of AGT (T704C) and VDR (1056T/C) genes don’t influence the risk of EH in population. However, AA-genotype of VDR gene in hypertensive women elevated risk of EH 3 times.

Single-nucleotide Polymorphisms of AGT, SOD2, CAT in Risk Estimates for Arterial Hypertension among Young People

Arterial hypertension is one of the most common cardiovascular diseases and one of the main causes of mortality and disability of population. Opportunity to predict emergence of arterial hypertension and to take preventive measures in pre-nosological diagnostics of disease arouse research interest in this issue. Possibility to predict progression of arterial hypertension based on polymorphic variants of AGT gene (C521T, rs4762) identification, which encodes angiotensinogen protein in combination with polymorphic variants of CAT (–262C/T, rs1001179), encoding catalase, and polymorphic variants of SOD2 (C47T, rs4880), encoding mitochondrial superoxide dismutase, are discussed in this article. Decrease of antioxidant enzymes (catalase and superoxide dismutase) activity leads to accumulation of reactive oxygen species in cells. They may activate NF-kB transcription factor, which increases expression of individual genes involved in sodium homeostasis and in blood pressure control, including angiotensinogen. Increased angiotensinogen concentration in blood constitutes a risk factor in arterial hypertension development. In our opinion, combination of polymorphic variants of AGT, CAT and SOD genes expands the possibilities of personalized medicine.Performed investigation involved 65 medical students of St Petersburg State University. DNA was extracted from epithelial cells of the oral cavity. Genotyping of DNA samples was determined by real-time PCR. Obtained results of our investigation enabled to reveal AGT genotypes associated with hypertension in 12 students. The article discusses combinations of TT and CT genotypes of AGT with unfavorable alleles of antioxidant enzymes.Carriers of heterozygous SOD2 genotype and homozygous CC genotype CAT are in more unfavorable conditions compared to carriers of the CC genotype SOD2 and СТ genotype CAT, as SOD2 is a key antioxidant enzyme protecting from ROS.

Effect of Genetic and Nongenetic Factors on the Clinical Response to Mineralocorticoid Receptor Antagonist Therapy in Egyptians with Heart Failure.

This prospective cohort study evaluated the association between the renin angiotensin aldosterone system genotypes and response to spironolactone in 155 Egyptian patients with heart failure with reduced ejection fraction (HFrEF). Genotype frequencies for AGT rs699 were: CC = 16%, CT = 48%, and TT = 36%. Frequencies for CYP11B2 rs1799998 were: TT = 33%, TC = 50%, and CC = 17%. After 6 months of spironolactone treatment, change in the left ventricular ejection fraction (LVEF) differed by AGT rs699 (CC, 14.6%; TC, 7.9%; TT, 2.7%; P = 2.1E‐26), and CYP11B2 rs1799998 (TT, 9.1%; TC, 8.7%; CC, 1.4%; P = 0.0006) genotypes. Multivariate linear regression showed that the AGT rs699 and CYP11B2 rs1799998 polymorphisms plus baseline serum potassium explained 71% of variability in LVEF improvement (P = 0.001), 63% of variability in serum potassium increase (P = 2.25E‐08), and 39% of the variability in improvement in quality of life (P = 2.3E‐04) with spironolactone therapy. These data suggest that AGT and CYP11B2 genotypes as well as baseline serum K are predictors of spironolactone response in HFrEF.

A Genome-Wide Association Study of Sprint Performance in Elite Youth Football Players

Pickering, C, Suraci, B, Semenova, EA, Boulygina, EA, Kostryukova, ES, Kulemin, NA, Borisov, OV, Khabibova, SA, Larin, AK, Pavlenko, AV, Lyubaeva, EV, Popov, DV, Lysenko, EA, Vepkhvadze, TF, Lednev, EM, Leońska-Duniec, A, Pająk, B, Chycki, J, Moska, W, Lulińska-Kuklik, E, Dornowski, M, Maszczyk, A, Bradley, B, Kana-ah, A, Cięszczyk, P, Generozov, EV, and Ahmetov, II. A genome-wide association study of sprint performance in elite youth football players. J Strength Cond Res 33(9): 2344-2351, 2019-Sprint speed is an important component of football performance, with teams often placing a high value on sprint and acceleration ability. The aim of this study was to undertake the first genome-wide association study to identify genetic variants associated with sprint test performance in elite youth football players and to further validate the obtained results in additional studies. Using micro-array data (600 K-1.14 M single nucleotide polymorphisms [SNPs]) of 1,206 subjects, we identified 12 SNPs with suggestive significance after passing replication criteria. The polymorphism rs55743914 located in the PTPRK gene was found as the most significant for 5-m sprint test (p = 7.7 × 10). Seven of the discovered SNPs were also associated with sprint test performance in a cohort of 126 Polish women, and 4 were associated with power athlete status in a cohort of 399 elite Russian athletes. Six SNPs were associated with muscle fiber type in a cohort of 96 Russian subjects. We also examined genotype distributions and possible associations for 16 SNPs previously linked with sprint performance. Four SNPs (AGT rs699, HSD17B14 rs7247312, IGF2 rs680, and IL6 rs1800795) were associated with sprint test performance in this cohort. In addition, the G alleles of 2 SNPs in ADRB2 (rs1042713 & rs1042714) were significantly over-represented in these players compared with British and European controls. These results suggest that there is a genetic influence on sprint test performance in footballers, and identifies some of the genetic variants that help explain this influence.

The AGT M235T (RS699, 4072T>C) polymorphism is not associated with elite weightlifting performance

It is now well established that genetic background influences an athlete’s ability to excel in different sport disciplines. Previous studies have demonstrated that among power athletes, single nucleotide polymorphism (SNP) in the AGT genotype (Thr-Thr), was significantly more prevalent among weightlifters compared to sprinters and jumpers indicating that despite the common features of these sport subtypes (short and very intense), they vary in their strength and speed abilities, as well as in their genetic make-up. The aim of the present study was to assess whether the AGT SNP can be used also to distinguish elite from national levels weightlifters. The AGT M235T genotype frequencies were assessed in 47 weightlifters (30 elite, 17 national level) and 86 non-athletes control. The Thr-Thr genotype was significantly higher among weightlifters (29.8%) compared to controls (12.8%) (p=0.048). Thr allele frequency was significantly higher among weightlifters (55.3%) compared to controls (37.8%) (p=0.021). However, there was no difference in the prevalence of the polymorphism between national level and elite athletes. In conclusion, the results suggest that the AGT polymorphism cannot predict elite competitive weightlifting performance.

Renin-angiotensin system gene polymorphisms and high blood pressure in Lithuanian children and adolescents

BackgroundEpidemiological studies have demonstrated the influence of environmental factors on HBP in the population of Lithuanian children, although the role of genetic factors in hypertension has not yet been studied. The aim of this study was to assess the distribution of AGTR1, AGT, and ACE genotypes in the Lithuanian child population and to determine whether these genotypes have an impact on HBP in childhood.MethodsThis cross-sectional study enrolled 709 participants aged 12–15 years. The subjects were genotyped for AGT (M235 T, rs699), AGTR1 (A1166C, rs5186), and ACE (rs4340) gene polymorphisms using real-time and conventional polymerase chain reactions. Blood pressure and anthropometric parameters were measured.ResultsThe prevalence of HBP was 38.6% and was more frequently detected in boys than in girls (47.9% vs. 29.5%; p < 0.001). No significant differences in the frequencies of the AGT or AGTR1 genotypes or alleles between boys and girls were observed, except for ACE genotypes. The mean SBP value was higher in HBP subjects with ACE ID genotype compared to those with ACE II homozygotes (p = 0.04). No significant differences in BP between different AGT and AGTR1 genotype groups were found. Boys who carried the ACE ID + DD genotypes had higher odds of having HBP than carriers of the ACE II genotype did (controlling for the body mass index (BMI): ORMH = 1.83; 95% CI, 1.11–3.02, p = 0.024; and controlling for waist circumference (WC): ORMH = 1.76; 95% CI, 1.07–2.92, p = 0.035). These associations were not significant among girls. The same trend was observed in the multivariate analysis – after adjustment for BMI and WC, only boys with ACE ID genotype and ACE ID + DD genotypes had statistically significantly increased odds of HBP (aOR = 2.05; 95% CI, 1.19–3.53 (p = 0.01) and aOR = 1.82; 95% CI, 1.09–3.04 (p = 0.022), respectively).ConclusionsThe evaluated polymorphisms of the AGT and AGTR1 genes did not contribute to the presence of HBP in the present study and may be seen as predisposing factors, while ACE ID genotypes were associated with significantly increased odds for the development of HBP in the Lithuanian child and adolescent population - especially in boys.

Association between ACE and AGT polymorphism and cardiovascular risk in acromegalic patients.

Whether the renin-angiotensin-aldosterone system plays a role or not in the development of cardiovascular morbidity in acromegaly patients is unknown. The aim of the study was to investigate the association between ACE (I/D) and AGT (M235T) gene polymorphisms and cardiovascular and metabolic disorders in the acromegaly. The study included one hundred and seventeen acromegalic patients (62F/55M, age: 50.2 ± 12.3 years) and 106 healthy controls (92F/14M, age: 41.4 ± 11.3 years). PCR method was used to evaluate the prevalence of ACE and AGT genotype. The genotypes of ACE polymorphism in acromegalic patients were distributed as follows; 41.0% (n: 48) for DD, 44.4% (n: 52) for ID and 14.5% (n: 17) for II genotype. The control group had significantly different distribution of the ACE polymorphism [48.1% (n: 51) for DD, 25.5% (n: 27) for ID and 26.4% (n: 28) for II genotype]compared to acromegalic group. Regarding AGT polymorphism, AGT-MT genotype was seen in 88.9% of the acromegalic patients while MM and TT genotype (9.4% and 1.7%, respectively) were present in the rest. The controls had similar distribution of the AGT genotype with the acromegaly group (80.2% MT genotype, 15.1% MM genotype and 4.7% TT genotype). Due to the small number of patients with TT allele (n: 2), T carriers for AGT genotype (AGT-MT+TT) were subgrouped and compared to those with AGT-MM group. ACE-DD, ID and II groups had similar anthropometric measures, blood pressure values and baseline GH and IGF-1 levels. Significantly higher baseline GH levels were found in AGT-MM group compared to T allele carriers [40 (16-60) vs. 12 (5-36)µg/L, p < 0.05]. The compared groups in both polymorphisms had similar fasting plasma glucose levels. Patients with ACE-II genotype had significantly higher HDL-C levels compared to those with ACE-DD and ACE-ID polymorphisms (p < 0.05) whereas there was no significant difference in lipid profile between AGT-MM group and AGT-T allele carriers. Moreover, the compared groups in both polymorphisms had similar distribution of hyperlipidemia, hypertension, impaired glucose metabolism (prediabetes or type 2 diabetes mellitus) and coronary artery disease. In terms of echocardiographic parameters, systolic and diastolic function was similar among the groups in ACE and AGT genotypes. Interestingly, AGT-MM group had higher mitral inflow Apeak values than T allele carriers (0.94 ± 0.46 vs. 0.73 ± 0.20; p = 0.051). No significant difference was observed in LV mass index values in acromegalic patients among the groups in both polymorphisms. Both ACE (I/D) and AGT (M235T) gene polymorphisms do not seem to have a significant effect on the development of clinical properties or cardiovascular comordities of acromegalic patients.

The influence of genetic polymorphisms on performance and cardiac and hemodynamic parameters among Brazilian soccer players.

This study investigated whether ACTN3 R577X, AMPD1 C34T, I/D ACE, and M235T AGT polymorphisms can affect performance tests such as jumping, sprinting, and endurance in 220 young male athletes from professional minor league soccer team from São Paulo Futebol Clube, Brazil. I/D ACE and M235T AGT polymorphisms were also analyzed according to cardiac and hemodynamic parameters. Athletes were grouped or not by age. DNA from saliva and Taqman assays were used for genotyping 220 athletes and the results were associated with performance tests. Ventricle mass, ventricle end-diastolic diameter, end-diastolic volume, and ejection fraction were assessed by echocardiogram. Arterial pressure, heart rate, and oximetry were assessed by a cardioscope. The main results of this study were that athletes who carried RR/RX (ACTN3) and DD (ACE) genotypes presented better performance during jump and sprint tests. On the other hand, athletes with ID/II genotype presented better results during endurance test, while AGT genotypes did not seem to favor the athletes during the evaluated physical tests. CC genotype (AMPD1) only favored the athletes during 10-m sprint test. Although there are environmental interactions influencing performance, the present results suggest that RR/RX ACTN3 and ACE DD genotypes may benefit athletes in activities that require strength and speed, while II ACE genotype may benefit athletes in endurance activities. This information could help coaches to plan the training session to improve the athletes' performance.

Genetic variants of ACE (Insertion/Deletion) and AGT (M268T) genes in patients with diabetes and nephropathy.

Diabetes mellitus (DM) has been a growing epidemic worldwide and poses a major socio-economic challenge. The leading cause of DM death is nephropathy due to end-stage renal disease (ESRD). This study aims to identify the possible association of I/D variants of the ACE gene and M268T (rs699) of the AGT gene of renin-angiotensin-aldosterone system (RAAS). Study subjects include 115 patients with DM, 110 with diabetic nephropathy (DN) and 110 controls. Fasting blood samples were collected for biochemical analyses and PCR amplification of specific regions of the ACE and AGT genes using primers. The distribution of ACE (I/D) II 28.8%, ID 35.6% and DD 35.6% while in DN II 24.5%, ID 41% and DD 34.5%. The AGT (M268T) genotypes were distributed in DM as TT 30.4%, MT 66.9% and MM 2.6% while in DN subjects TT 56.4%, MT 42.7% and MM 0.9%. Significant differences were observed in the DD genotype and D allele of the ACE gene and the TT genotype and T allele of AGT genes between diabetic patients with and without nephropathy. The study may conclude that the D allele polymorphism in the ACE gene and the T allele polymorphism in AGT gene may be considered as genetic risk factors for the development of nephropathy in diabetes.

Renin-Angiotensin System Genetic Polymorphisms and Brain White Matter Lesions in Older Australians

White matter lesions (WMLs), seen as hyperintensities on T2-weighted magnetic resonance imaging brain scans, are common in the brains of healthy older individuals. They are thought to be related to cerebral small vessel disease and to have a genetic component to their aetiology, and hypertension is thought to be an important risk factor. Genetic polymorphisms in hypertension-related genes may therefore be associated with the formation of WMLs. In this study, a sample of 445 Australians aged 60-65 years was drawn from a larger longitudinal epidemiological study, the Personality and Total Health Through Life Project. The associations of single nucleotide polymorphisms (SNPs) in the genes encoding angiotensinogen (AGT, rs699), angiotensin-converting enzyme (ACE, rs4362), and angiotensin II receptor type 1 (AGTR1, rs5182) with WMLs were examined. No individual SNPs showed a significant association with WMLs for the whole sample. When the cohort was stratified by sex, ACE rs4362 and AGT rs699 showed significant associations with WMLs in men only (P = 0.01 and P = 0.03, respectively), and remained significant after controlling for hypertension. Although the AGTR1 SNP did not show any association with WMLs, the interaction of the AGT rs699 and AGTR1 rs5182 SNPs with WMLs was significant before (P = 0.03) and after adjustment for hypertension (P = 0.045). The results provide evidence for association of polymorphisms in the renin-angiotensin system genes with WMLs, independent of hypertension. Male-only associations with WMLs were found for the AGT rs699 and ACE rs362 polymorphisms. Moreover, for the entire sample an interaction between AGT and AGTR1 rs5182 genotypes on WMLs was observed.

Relation of RAS Gene Polymorphisms with Impaired Glucose Tolerance in Patient with End Stage Renal Failure

Renin angiotensin system (RAS) is a system that is the role of renal hemodynamics, blood pressure and fluid electrolyte balance regulation with progression to end-stage renal disease (ESRD). Angiotensin II (AII),the main mediator of this system, is thought to cause a functional impairment in insulin receptor and post receptor signaling pathways. Our aim; was to show the relation of angiotensin-converting enzyme (ACE), angiotensin II receptor type 1 (AT1 R) and angiotensinogen gene (AGT) polymorphisms, that cause genetic susceptibility to over activation of RAS, to glucose intolerance in patient with end stage renal failure. The study included one hundredth patients. Based on fasting plasma glucose values and oral glucose tolerance test second hours glucose values, patients were grouped as normal patients and patients with glucose intolerance (impaired fasting glycemia (IFG), impaired glucose tolerance (IGT) and diabetes mellitus (DM)). Insulin resistance was calculated by HOMA-IR method and insulin sensitivity index was calculated by ISI-S method. ACE, AT1 R, AGT polymorphisms were detected by polymerase chain reaction (PCR) method. There was no statistically significant difference between distribution of ACE, AT1R and AGT genotypes and glucose intolerance groups, and insulin resistance. There was a statistically significant difference between MM and TT genotypes and average insulin resistance values (p < 0,04). We have obtained results suggesting a relation between ACE gene D allele and glucose intolerance in patients with end stage renal failure (p=0.06). Moreover, a relation has been shown between AGT gene T allele and insulin resistance (p=0.04).

Effect of specific ADRB1/ADRB2/AGT genotype combinations on the association between survival and carvedilol treatment in chronic heart failure

The aim of the present study was to determine whether carvedilol-treated chronic heart failure patients have a different prognosis when stratified for a specific combination of a gain-of-function genotype of the adrenergic β-1 receptor gene (ADRB1) (Arg389-homozygous), two gain-of-function genotypes of the angiotensinogen gene (AGT) (Thr174-homozygous and Thr235-homozygous), and a downregulated genotype of the adrenergic β-2 receptor gene (ADRB2) (Gln27-carrier). Genotyping of 618 patients was carried out using the Sequenoms MassARRAY genotyping system. Outcome was all-cause mortality and statistics were calculated using a multivariable Cox proportional hazards model. Internal validation was performed using the bootstrap procedure. Eighty-seven of the 618 patients included in the study were treated with carvedilol. There was a significant interaction between the outcome of carvedilol treatment and the combination of the gain-of-function ADRB1 genotype (Arg389-homozygous) and the gain-of-function AGT genotype (Thr174-homozygous) (P(interaction)=0.003; hazard ratio 2.19, 95% confidence interval 1.26-3.78, P=0.005). There was also a significant interaction when the downregulated ADRB2 genotype (Gln27-carrier) was added to the ADRB1/AGT combination (P(interaction)=0.0005; hazard ratio 2.67, 95% confidence interval 1.51-4.72, P=0.0007). Two hundred and four patients were treated with metoprolol. There was no interaction between metoprolol treatment and the specific genotype combinations as there was no difference in the overall survival. The validity of the results was supported by the bootstrap procedure. We found a doubling of the hazard of mortality in carvedilol-treated patients with the combination of the gain-of-function ADRB1 genotype (Arg389-homozygous), the gain-of-function AGT genotype (Thr174-homozygous), and the downregulated ADRB2 genotype (Gln27-carrier). This might be valuable when stratifying chronic heart failure patients to the right β-blocker therapy.

E0026 Association between the M235T, T174M polymorphism of the angiotensinogen gene and left ventricular hypertrophy in essential hypertension in Kazakans

ObjectiveTo investigate whether the M235T, T174M polymorphisms of the angiotensinogen gene were associated with left ventricular hypertrophy (LVH) in Xinjiang Kazakans with essential hypertension.Methods86 patients with essential hypertension and left...

INTERRELATION OF GENE POLYMORPHISM AND ENDOTHELIUM DYSFUNCTION IN UZBEK HYPERTENSIVE PATIENTS: PP.21.337

Background: Genetic elements contribute to 30–50% of the blood pressure variability. The underlying pathological defect in essential hypertension (EH) is due, at least in part, to endothelial dysfunction (ED). ED is recognized as an early stage in the pathogenesis of EH. Aim of the study was to evaluate the association of gene polymorphisms (ACE/ID, AGT/M235T, AT1R/A1166C, CYP11B2/C344T, BKRB2/ + 9–9, ecNOS/4a4b, GNB3/C825T, ARB2/Gln27Glu) with ED in Uzbek hypertensive men. Methods: The study included 174 nonsmoking men (46.8 ± 9.6 yr) with untreated EH of stage I-II. The total cholesterol (TC), triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) levels were determinated. Low-density lipoprotein cholesterol (LDL-C) level was calculated by the Friedewald formula. Microalbuminuria was defined as an albumin urinary excretion (AUE) level by immunoturbidimetric assay. Carotid intima-media thickness (IMT) was measured by high-resolution ultrasound. ED was evaluated by measuring of the flowmediated dilatation (FMD) of the brachial artery (BA) with a 7.5 MHz linear array transducer. Genomic DNA was extracted from peripheral blood. PCR-RFLP-based analysis of gene polymorphisms (GP) was performed. Statistical analysis was performed using a Microsoft Office Excel 2007 and Statistica v6.0. Results: Patients were divided into two groups: with δFMD>10% and δFMD < 10% for the determination of GP association with ED. Only the T-allele and MT-, TT-genotypes of the AGT gene were associated with an increased risk for ED: OR 3.18 (95% CI: 1.80–5.63); OR 2.24 (95% CI: 1.08–4.66); OR 15.94 (95% CI: 0.95–268.79). Multivariate logistic regression analysis (dependent variable: δFMD; independent variables: AGT genotype status, age, BMI, SBP, DBP, TC, HDL-C, IMT, AUE, atherogenity index, BA baseline diameter) confirmed the negative association between the MM genotype of the AGT gene, positive association between IMT and ED. We did not find a clear association of ED with other GP. Carriers of C-allele of AT1R gene, -9-allele of B2BKR gene and 4a-allele of ecNOS gene have more disorders of FMD. Conclusions: Only the TT genotype of AGT gene was significantly associated with the risk of ED.

Physical Training does not Influence Vasodilatation Responses in Individuals with M235T AGT and I/D ECA Gene Polymorphisms

We hypothesized that: 1)Reflex muscle vasodilatation to exercise is attenuated in individuals with 235T or D alleles and 2)Physical training would improve muscle vasodilatation responses in these individuals.Methods108 healthy individuals were genotyped for the M235T AGT (MM=20; MT=49; TT=39) and I/D ACE (DD=38; DI=48; II=22) genes variants. Mean blood pressure (MBP) and forearm blood flow (FBF, plethysmography) were evaluated at rest and at 30% handgrip exercise. Physical training was performed for 17 weeks (3 running sessions/week).ResultsResting forearm vascular conductance (FVC) and MBP were similar among AGT or ACE genotypes. During exercise, FVC increased significantly and similarly among MM, MT and TT (3.6±0.4; 3.3±0.2; 3.6±0.2 units, respectively, P=.91) and DD, DI and II (3.4±0.2; 3.6±0.3; 3.3±0.3 units, respectively, P=.92). Physical training significantly increased peak VO2(P=.001). Resting FVC was unchanged by physical training. Physical training improved slightly and similarly FVC responses to exercise in MM, MT and TT (4.1±0.5; 3.8±0.2; 3.8±0.3 units, respectively, P=.81) and DD, DI and II (3.6±0.2; 4.0±0.3; 3.7±0.4 units, respectively, P=.38).ConclusionsM235T AGT and the I/D ACE gene polymorphisms do not influence reflex muscle vasodilatation to exercise and the vascular response to physical training in healthy individuals.

Gene polymorphism of the renin-angiotensin system in six ethnogeographic regions of Belarus

The insertion/deletion polymorphism of the angiotensin-converting enzyme gene (ACE) and the T174M polymorphism of the angiotensinogen gene (AGT) have been studied in six ethnic/geographic regions of Belarus. Significant intrapopulation differences in ACE genotype frequencies have been found for the northern and eastern regions (the Dvina and Dnepr basins, respectively). Significant differences in the AGT genotype frequencies have been found between populations of the Dnepr basin and populations of all other Belarusian regions. The allele and genotype frequencies of the genes studied in the Belarusian population and populations of other regions of the world have been compared. The frequencies of the insertion (I) and deletion (D) alleles of the ACE gene in the Belarusian population are 50.7 and 49.3%, respectively, which is similar to these frequencies in European countries. The frequency of the M allele of the AGT gene in Belarus is 16.6%, which is higher than its frequency in populations of European, African, and Asian origins.

The M235T polymorphism of the AGT gene modifies the risk of coronary artery disease associated with the presence of hypercholesterolemia

Atherosclerosis is an inflammatory disease resulting from interactions between various genetic and non-genetic factors. Angiotensinogen gene (AGT) belongs to polymorphic candidate genes. Recent evidence show that many traditional risk factors of coronary artery disease (CAD) influence synthesis of AGT. This report focuses on the interactions between M235T polymorphism of AGT gene and traditional risk factors of CAD. 255 subjects, including 158 patients with angiographically confirmed CAD and 97 blood donors without history of cardiovascular diseases were studied. M235T polymorphism of the AGT gene was genotyped using PCR-RFLP method. To determine the possible interactions of AGT genotypes and traditional risk factors of CAD the attributable proportion due to interaction (AP) and synergy models were used. The frequency of 235T allele carriers was significantly higher in patients than in controls (77.8 vs. 62.9, OR = 2.20, 95% CI; 1.10-4.40, P = 0.026, in multivariate logistic regression model). We found the existence of interaction between the 235T allele carrier-state and hypercholesterolemia (total cholesterol > or = 5 mmol/l) increasing the risk of CAD (SI = 3.39, 95% CI; 1.33-8.66, AP = 0.65, 95% CI; 0.39-0.91). The 235T allele also interacted with elevated LDL cholesterol levels (> or = 3 mmol/l) (AP = 0.49, 95% CI; 0.20-0.96), but not with the hypertension, overweight/ obesity and cigarette smoking. The 235T allele increases the risk of CAD associated with the presence of hypercholesterolemia.

Abstract 2092: Effect Of Recipient Genotype On Donor Cardiac Allograft Function In Children And Young Adults

Background The renin-angiotensin-aldosterone (RAAS) and adrenergic receptor (ADR) genotypes affect cardiac function in heart failure. It is not known if recipient genotype affects function of the transplanted heart. We investigated the influence of recipient RAAS or ADR genotype on cardiac function and outcomes after transplant (Tx). Methods Patients (Pts) &lt; 25 yrs old, post cardiac Tx, were enrolled (2003–06) and genotyped for polymorphisms in genes associated with RAAS upregulation (ACE-D, AGTR1-C, AGT-G, CYP11B2-G and CMA1-A) and β-ADR downregulation (β1Arg389 and β2Gly16). Hetero- or homozygosity for the high risk allele was considered a high-risk genotype. Univariate associations between genotypes and incidence of rejection, cardiac dysfunction (hemodynamic/echocardiographic), graft vasculopathy (GV), death and reTx were assessed via logistic or linear regression models with time dependent models as needed. Results Of 222 pts transplanted, 107 pts were studied. Age at Tx was 8.4±6.8 yrs (follow-up, 6.3±5.3 yrs; 42% male). The high risk allele frequency was: ACE 51%, AGTR1 23%, AGT 59%, CYP 35%, CMA 42%, β1Arg389 74% and β2Gly16 37% (in Hardy-Weinberg equilibrium). During follow-up, 81% pts had rejection, 51% graft dysfunction, 13% developed GV, 7% died and 8% were re-transplanted. 24% pts were receiving ACE/Angiotensin receptor inhibitors and 5% were receiving β-blockers at 5 yrs post-Tx. The presence of a high risk AGT or AGTR genotype was associated with greater severity of graft dysfunction at last follow-up (p=0.05), elevated CVP and PA pressures (p&lt;0.001) and higher mortality. ADR genotype had no effect on outcomes. Cumulatively, a higher number of homozygous high risk RAAS genotypes was associated with a higher incidence of rejection (Hazard ratio/HR,1.3), graft dysfunction (HR,1.5) and higher probability of death (HR,2.5) (p&lt;0.05). Conclusion RAAS polymorphisms in the recipient are associated with higher mortality after cardiac Tx possibly related to greater impairment of graft function with rejection. Whether wider use of RAAS inhibitors in this high risk cohort can improve outcomes after Tx requires further investigation. The lack of effect of the ADR genotype may relate to sympathetic denervation of the transplanted heart.

Effect of the angiotensinogen genotype on experimental hypertension in mice

Polymorphisms of the angiotensinogen (Agt) gene may affect blood pressure. We used a mouse model to test for the role of the Agt genotype in low-renin or high-renin forms of hypertension. Mice bearing one, two, three, or four copies of the Agt gene underwent renal artery clipping to induce high-renin two-kidney, one-clip renovascular hypertension (2K1C), or uninephrectomy, salt loading, and application of deoxycorticosterone-acetate (DOCA) pellets to induce low-renin mineralocorticoid hypertension. Appropriate control animals were also studied. Blood pressure was measured by tail cuff as well as by direct intra-arterial recordings. There was a small effect of the Agt genotype on baseline blood pressure before induction of hypertension. The extent of 2K1C hypertension was not affected by the genotype. In contrast, there was a marked gene-dose effect on DOCA-hypertension (21.2 mmHg over all genotypes). Treatment of DOCA mice with the angiotensin II type 1 receptor antagonist abolished the genotype effect on blood pressure and left ventricular hypertrophy. There was a trend towards less suppression of endogenous aldosterone by DOCA treatment with increasing number of Agt gene copies. We conclude that the Agt genotype exerts a marked effect on blood pressure in a low-renin form of hypertension but no effect in the face of stimulated renin, at least in mice.

Renin–angiotensin system gene polymorphisms: association with susceptibility to Henoch–Schonlein purpura and renal involvement

The clinical course of Henoch-Schönlein Purpura (HSP) in children is variable, with some patients having a much more rapidly progressing course than others. We investigated whether polymorphisms of the renin-angiotensin system (RAS) genes are involved in HSP. Three RAS genotypes were examined in 114 children with HSP and in 164 healthy children: the angiotensin I converting enzyme (ACE) insertion/deletion polymorphism, the M235T mutation in the angiotensinogen gene (Agt), and the A1166C in the angiotensin II type I receptor (AT1R) gene. Significant differences were observed between HSP patients and control group in the frequency of ACE and Agt genotypes (p=0.004 and p=0.003, respectively). The TT genotype of Agt gene was associated with a 3.5-fold increased risk for Henoch-Schönlein nephritis (HSN) compared with the MM/MT genotype (odds ratio, 3.5; 95% confidence interval, 1.2-10.4). There was a trend to a higher prevalence of the TT genotype of the Agt gene among patients with nephrotic range proteinuria when compared to the patients with mild proteinuria, although the difference did not reach a statistical significance. The results of this study suggest that polymorphisms of ACE gene and Agt gene likely influence the risk of developing HSP. However, among the three genes of the RAS studies, only Agt gene was associated with the susceptibility to HSN. RAS gene polymorphisms studied are not associated with the presence of nephrotic range proteinuria. Additional studies are warranted to verify the correlation between RAS gene polymorphisms and susceptibility to HSP.