The angiotensinogen gene polymorphism is associated with heart failure among Asians.
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ABSTRACT:
SUBMITTER: Jiang WL
PROVIDER: S-EPMC3936209 | biostudies-other | 2014
REPOSITORIES: biostudies-other
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Project description:Adenosine (Ado) is an important cardioprotective agent. Since endogenous Ado levels are affected by the enzyme Ado deaminase (ADA), polymorphisms within the ADA gene may exert some effect on chronic heart failure (CHF). This study applied a case-control investigation to 300 northern Chinese Han CHF patients and 400 ethnicity-matched healthy controls in which nine single-nucleotide polymorphisms (SNPs) of ADA were genotyped and association analyses were performed. Odds ratios (ORs) with 95% confidence intervals (CI) were used to assess the association. Overall, rs452159 polymorphism in ADA gene was significantly associated with susceptibility to CHF under the dominant model (p = 0.013, OR = 1.537, 95% CI = 1.10-2.16), after adjustment for age, sex, and traditional cardiovascular risk factors. No difference in genotype distribution and allele frequency for the rs452159 according to the functional New York Heart Association class was found. Furthermore, the values of left ventricular ejection fraction, left-ventricle end-diastolic diameter or left-ventricle end-systolic diameter did not differ significantly among the different rs452159 genotype CHF patients. Although further studies with larger cohorts and other ethnicities are required to validate the conclusions, the findings of this study potentially provide novel insight into the pathogenesis of CHF.
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Project description:Renin is the rate-limiting enzyme of the renin-angiotensin system cascade, which drives the pathophysiological progression of heart failure. Species differences in the amino acid sequence of the catalytic domain of renin limit evaluations of the potency and efficacy of human renin inhibitors in animal models, and a high dose of inhibitors is usually needed to show its organ-protective effects in rodents. In the present study, we developed a novel murine heart failure model (triple-tg) to enable us to evaluate the cardioprotective effect of renin inhibitors at more relevant doses for humans, by cross-breeding calsequestrin transgenic (CSQ-tg) mice with human renin and human angiotensinogen double-transgenic mice. The triple-tg mice exhibited increased plasma renin activity, worsened cardiac hypertrophy, and higher mortality compared to CSQ-tg mice. Triple-tg mice treated with 10 mg·kg-1 of TAK-272 (imarikiren/SCO-272), an orally active direct renin inhibitor, exhibited improvements in heart failure phenotypes, such as cardiac hypertrophy and survival rate; however, a dose of 300 mg·kg-1 was required to improve symptoms in CSQ-tg mice. Our results suggest that this newly generated triple-tg heart failure model is useful to evaluate the cardioprotective effects of human renin inhibitors at clinically relevant doses, thereby minimizing the concerns of off-target effects related to much higher drug exposure than that achieved in clinical study.
| S-EPMC7193172 | biostudies-literature
Project description:BackgroundCardiac remodeling is generally an adverse sign and is associated with heart failure (HF) progression. NFkB, an important transcription factor involved in many cell survival pathways, has been implicated in the remodeling process, but its role in the heart is still controversial. Recently, a promoter polymorphism associated with a lesser activation of the NFKB1 gene was also associated with Dilated Cardiomyopathy. The purpose of this study was to evaluate the association of this polymorphism with clinical and functional characteristics of heart failure patients of different etiologies.MethodsA total of 493 patients with HF and 916 individuals from a cohort of individuals from the general population were investigated. The NFKB1 -94 insertion/deletion ATTG polymorphism was genotyped by High Resolution Melt discrimination. Allele and genotype frequencies were compared between groups. In addition, frequencies or mean values of different phenotypes associated with cardiovascular disease were compared between genotype groups. Finally, patients were prospectively followed-up for death incidence and genotypes for the polymorphism were compared regarding disease onset and mortality incidence in HF patients.ResultsWe did not find differences in genotype and allelic frequencies between cases and controls. Interestingly, we found an association between the ATTG1/ATTG1 genotype with right ventricle diameter (P = 0.001), left ventricle diastolic diameter (P = 0.04), and ejection fraction (EF) (P = 0.016), being the genotype ATTG1/ATTG1 more frequent in patients with EF lower than 50% (P = 0.01). Finally, we observed a significantly earlier disease onset in ATTG1/ATTG1 carriers.ConclusionThere is no genotype or allelic association between the studied polymorphism and the occurrence of HF in the tested population. However, our data suggest that a diminished activation of NFKB1, previously associated with the ATTG1/ATTG1 genotype, may act modulating on the onset of disease and, once the individual has HF, the genotype may modulate disease severity by increasing cardiac remodeling and function deterioration.
| S-EPMC2897791 | biostudies-literature
Project description:BackgroundIt is well known that familial sick sinus syndrome (SSS) is caused by functional alterations of ion channels and gap junction. Limited information is available on the mechanism of age-related non-familial SSS. Although evidence shows a close link between arrhythmia and the renin-angiotensin system (RAS), it remains to be determined whether the RAS is involved in the pathogenesis of non-familial SSS.MethodsIn this study, 113 patients with documented non-familial SSS and 125 controls were screened for angiotensinogen (AGT) and gap junction protein-connexin 40 (Cx40) promoter polymorphisms by gene sequencing, followed by an association study. A luciferase assay was used to determine the transcriptional activity of the promoter polymorphism. The interaction between nuclear factors and the promoter polymorphism was characterized by an electrophoretic mobility shift assay (EMSA).ResultsAssociation study showed the Cx40 -44/+71 polymorphisms are not associated with non-familial SSS; however, it indicated that four polymorphic sites at positions -6, -20, -152, and -217 in the AGT promoter are linked to non-familial SSS. Compared to controls, SSS patients had a lower frequency of the G-6A AA genotype (OR 2.88, 95% CI 1.58-5.22, P?=?0.001) and a higher frequency of the G allele at -6 position (OR 2.65, 95% CI 1.54-4.57, P?=?0.0003). EMSA and luciferase assays confirmed that nucleotide G at position -6 modulates the binding affinity with nuclear factors and yields a lower transcriptional activity than nucleotide A (P<0.01).ConclusionG-6A polymorphism, which modulates the transcriptional activity of the AGT promoter, may contribute to non-familial SSS susceptibility.
| S-EPMC3252346 | biostudies-literature
Project description:A major challenge in prevention and early treatment of acute cardiorenal syndrome (CRS) is the lack of high-performance predictors. To test the hypothesis that urinary angiotensinogen (uAGT) is an early predictor for acute CRS and 1-year prognosis in patients with acute decompensated heart failure (ADHF), we performed a prospective, two-stage, multicenter cohort study in patients with ADHF. In stage I (test set), 317 patients were recruited from four centers. In stage II (validation set), 119 patients were enrolled from two other centers. Daily uAGT levels were analyzed consecutively. AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guidelines. In stage I, 104 (32.8%) patients developed AKI during hospitalization. Daily uAGT peaked on the first hospital day in patients who subsequently developed AKI. After multivariable adjustment, the highest quartile of uAGT on admission was associated with a 50-fold increased risk of AKI compared with the lowest quartile. For predicting AKI, uAGT (area under the receiver-operating characteristic curve [AUC]=0.84) outperformed urinary neutrophil gelatinase-associated lipocalin (AUC=0.78), the urinary albumin/creatinine ratio (AUC=0.71), and the clinical model (AUC=0.77). Survivors in stage I were followed prospectively for 1 year after hospital discharge. The uAGT level independently predicted the risk of 1-year mortality (adjusted odds ratio, 4.5; 95% confidence interval, 2.1 to 9.5) and rehospitalization (adjusted odds ratio, 3.6; 95% confidence interval, 1.6 to 5.7). The ability of uAGT in predicting AKI was validated in stage II (AUC=0.79). In conclusion, uAGT is a strong predictor for acute CRS and 1-year prognosis in ADHF.
| S-EPMC4520164 | biostudies-literature
Project description:The plasmatic angiotensinogen (AGT) level has been associated with essential hypertension. Linkage analysis has found a relationship between the AGT gene locus and hypertension in the Mexican-American population, but studies have failed to identify genetic variants associated with hypertension or plasma AGT levels. This study analyzes the relationship between polymorphisms in the AGT gene and plasmatic AGT levels in Mexican population.Nine polymorphisms in AGT gene were genotyped, and plasma AGT level was determined by enzyme-linked immunosorbent assay.Differences in AGT plasma levels were associated with 2 polymorphisms: T-20G, TT = 25.3 ± 8.3 versus TG + GG = 21.6 ± 8.8 ?g/mL; P = 0.008 and C3389T (T174M), CC = 25.8 ± 9.9 versus TC + TT = 20.5 ± 5.4 ?g/mL; P = 0.0002. Haplotype 2 was associated with low plasma AGT (-5.1 ?g/mL [95% confidence interval: -8.6 to -1.6], P = 0.004) and Haplotype 8 was associated with high plasma AGT (6.5 ?g/mL [95% confidence interval: 2.5 to 10.6], P = 0.001). This association remained after adjustment for covariates. A Likelihood Ratio Test for haplotype-phenotype association adjusted for covariates resulted in ? = 38.9, P = 0.0005. The total effect of the haplotypes on plasma AGT level variance was 19.5%. No association was identified between haplotypes and quantitative traits of blood pressure.Two polymorphisms (T-20G and C3389T) and 2 haplotypes (H2 and H8) showed an association with plasma AGT levels in Mexican population.
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Project description:Hypertension is a serious risk factor for cardiovascular disease. Like other complex disease, hypertension is caused by a combination of genetic and environmental factors. The renin-angiotensin system plays an important role in the regulation of blood pressure. Angiotensinogen (AGT) gene is associated with essential hypertension in Caucasians, Japanese, and Asian-Indian subjects. AGT gene may also be associated with cardiac hypertrophy, coronary atherosclerosis, and microangiopathy related cerebral damage. Human AGT gene has a C/A polymorphism at nucleoside 11525 (rs7079) that is located in the 3'-untranslated region (3'-UTR) and is modestly associated with increased blood pressure. We show here that miR-31 and miR-584 bind strongly to the hAGT 3'-UTR containing 11525C allele compared with 11525A allele. We also show that transfection of miR-31 and miR-584 downregulates the hAGT mRNA and protein levels in human liver cells. These studies may provide new therapeutic approach to reduce hypertension.
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Project description:Tumor necrosis factor ? (TNF?) may contribute to the pathologic process of congestive heart failure (CHF). TNF? signaling occurs through two receptors; TNFR1 (TNFRSF1A) and TNFRII (TNFRSF1B). In humans a single nucleotide polymorphism (rs1061622 in TNFRSF1B exon 6; T587G) encodes two different amino acids (M196R) in the transmembrane region. The 587G allele is associated with greater severity and/or prevalence of some inflammatory diseases, but its role in CHF in unknown. This study sought to test the hypothesis that the 587G allele is associated with a worse outcome or more severe phenotype in CHF. Peripheral blood DNA was isolated and genotyped from 379 heart failure patients enrolled in a genetic outcome study (GRACE); (44.7% ischemic, 70.4% male, 8.5% black race, age 55.6 ± 11.7 yr (SD), LVEF 24.5 ± 8.3%, NYHA 2.53 ± 0.64). Genotyping was performed by PCR-RFLP. Cardiac function was assessed from medical records at study entry. The distribution of genotypes in this population was 54% T/T, 38.4% G/T and 7.7% G/G. Mean LV ejection fraction (T/T 24.4 ± 8.2, T/G 25.0 ± 8.4, G/G 23.3 ± 8.6, n=352, p=ns) and LV end-diastolic dimensions (T/T 6.57 ± 0.93, T/G 6.53 ± 1.0, G/G 6.57 ± 0.78, n=211, p=ns) were comparable in all groups. Transplant-free survival (median 23 months (range 1-62 months) did not vary by genotype (p=0.95). A lack of effect (p=0.74) on transplant-free survival was also observed in a subset of patients with ischemic heart failure (n=169). The TNFRSF1B 587G allele is not associated with the severity of heart failure phenotype or clinical outcomes in patients with chronic CHF.
| S-EPMC3592567 | biostudies-literature
Project description:Background:Kawasaki disease (KD) is an acute vasculitis disease that commonly causes acquired heart disease in children. Coronary artery aneurysm (CAA) is a major complication of KD. However, the pathogenesis of KD remains unclear. The results of a genome-wide association study (GWAS) showed that two functional single-nucleotide polymorphisms (SNPs; rs699A>G and rs5050T>G) in the angiotensinogen (AGT) gene were related to cardiovascular disease susceptibility. The purpose of our study was to estimate the relationship between the two GWAS-identified AGT gene polymorphisms and the risk of CAA in Southern Chinese children with KD. Methods:We genotyped the two AGT gene polymorphisms (rs699A>G and rs5050T>G) in 760 KD cases and 972 healthy controls. We used the odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the degree of the associations. Results:These two AGT gene polymorphisms were not associated with a risk of KD relative to the controls, but after adjusting for sex and age, the carriers of the rs5050G allele with TG/GG vs TT had an adjusted OR = 1.56, 95% CI = 1.01-2.41, and P = 0.044 relative to the carriers of the rs5050TT genotype. The susceptibility to CAA was more predominant in KD patients younger than 12 months old. Conclusions:Our results indicate that the AGT gene polymorphism rs5050T>G may increase the risk of CAA in children with KD, especially those who are younger than 12 months. These results need to be verified by a validation study with a larger sample size.
| S-EPMC6335657 | biostudies-literature
Project description:BACKGROUND: Angiotensinogen (AGT) constitutes a central component of the renin-angiotensin system that controls the systemic blood pressure and several other cardiovascular functions and may play an important role in atherosclerosis pathways. In this study, we employed TaqMan genotyping assays to evaluate the role of 8 AGT variants in primary hypertension (HTN), type 2 diabetes mellitus (T2DM), and obesity as a possible trigger of coronary artery disease (CAD) in a population of 4615 angiographed native Saudi individuals. METHODS: Linkage analysis was done by using the Affymetrix Gene Chip array, sequencing by using the MegaBACE DNA analysis system and genotyping accomplished by TaqMan chemistry using the Applied Biosystem real-time Prism 7900HT Sequence Detection System. RESULTS: Six variants, rs2067853 GG [Odds ratio(95% Confidence Interval) = 1.44(1.17-1.78); p = 0.001], rs7079 [1.49(1.20-1.85); p < 0.0001], rs699 G [1.19(1.08-1.13); p < 0.0001], rs3789679 A [1.51(1.14-1.99); p = 0.004], rs2148582 GG [1.31(1.11-1.55); p = 0.002] and rs5051 TC + CC [1.32(1.13-1.60); p = 0.001] conferred risk for HTN (3521 cases versus 1094 controls). The rs2067853 (p = 0.042), rs699G (p = 0.007) and rs5051 (p = 0.051) also conferred risk for myocardial infarction (MI; 2982 vs 1633), while rs3789679 A (p < 0.0001) and GA + AA (p < 0.0001) as well as rs4762G (p = 0.019) were associated with obesity (1576 vs 2458). However, while these variants appeared to be also associated with CAD (2323 vs 2292), only the rs7079G (p = 0.035) retained its significant relationship. Interestingly, among the haplotypes constructed from these SNPs, the baseline 8-mer haplotype, GGTGGGGT (?² = 7.02; p = 0.0081) and another GGCGGAGT (?² = 5.10; p = 0.024), together with several of their derivatives were associated with HTN. T2DM was associated with two 8-mer haplotypes, GGTAGGAC (?2 = 5.66; p = 0.017) and ATTGAGAC (?² = 5.93; p = 0.015), obesity with GGCGGAGT (?² = 9.49; p = 0.0021) and MI was linked to ATTGGGAC (?² = 6.68; p = 0.010) and GGTGGGAT (?² = 4.25; p = 0.039). Furthermore, several causative haplotypes were also shared among the risk traits as well as with CAD. CONCLUSION: These results point to AGT as independently conferring risk for various cardiovascular traits, and possibly interacting with these traits in events leading to atherosclerosis.
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