Relationship between AGT rs2493132 polymorphism and the risk of coronary artery disease in patients with NAFLD in the Chinese Han population

ObjectiveTo investigate the relationship between angiotensin (AGT) rs2493132 gene polymorphism and the risk of developing non-alcoholic fatty liver disease (NAFLD) and coronary artery disease (CAD) in the Chinese Han population.MethodsPolymerase chain reaction was performed to determine AGT genotypes. Anthropometric and clinical data were investigated and statistically analyzed in the clinical laboratory department of Qingdao Municipal Hospital.ResultsThe AGT rs2493132 CT + TT genotype was an important risk factor for CAD in patients with NAFLD and NAFLD + CAD in healthy controls. The AGT rs2493132 T allele increased the risk of NAFLD + CAD in healthy controls. The AGT rs2493132 CT + TT genotype and T allele also significantly increased the risk of CAD in patients with NAFLD after adjustments for age, sex, and body mass index. In addition, AGT rs2493132 T allele carriers showed higher total cholesterol (TC) and low-density lipoprotein (LDL) levels compared with non-carriers.ConclusionsThe AGT rs2493132 CT + TT genotype and T allele significantly increased the risk of developing CAD in patients with NAFLD in the Chinese Han population. The AGT rs2493132 T allele was associated with increased serum TC and LDL levels.     

Association between T174M polymorphism in the angiotensinogen gene and risk of coronary artery disease: a meta-analysis

Background Angiotensinogen (AGT) T174M gene polymorphism has been suggested to be linked to risk of coronary artery disease, however, results from studies of this association have been inconsistent. In this study, we assess the relationship between AGT T174M gene polymorphism and coronary artery disease. Methods We conducted a meta-analysis of 18 case-control studies with 8,147 coronary artery disease cases and 5,344 controls in Google scholar, PubMed, Cochrane Library and China National Knowledge Infrastructure (CNKI) databases to identify eligible studies published by July, 2012. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated from these studies. Results Overall, a significant association was found between angiotensinogen T174M polymorphism and coronary artery disease risk when all studies were pooled into the meta-analysis (TT vs. MM: OR = 0.53, 95% CI = 0.40–0.71; dominant model: OR = 1.16, 95% CI = 1.01–1.35; recessive model: OR = 0.54, 95% CI = 0.40–0.72). In a stratified analysis, the results indicate a significant associa?tion in Caucasians suffering from coronary stenosis (TT vs. MM: OR = 0.38, 95% CI = 0.23–0.63; recessive model: OR = 0.39, 95% CI = 0.23–0.64). No significant increased risk for coronary artery disease was found in Asians. Conclusions The meta-analysis indicate a significant associa?tion of T174M polymorphism with coronary stenosis risk in Caucasians.     

Response to genetic manipulations of liver angiotensinogen in the physiological range

Genetic variation in the human angiotensinogen gene (AGT) influences plasma AGT concentration and susceptibility to essential hypertension by a mechanism that remains to be clarified. When one or two additional copies of the gene were inserted by gene titration (by homologous recombination with gap-repair at the AGT locus), both plasma AGT and arterial pressure were elevated in the physiological range in the mouse. The causal dependency between plasma AGT and blood pressure and the relative contribution of the various tissues that express AGT to these two phenotypic parameters remained to be determined. To address these issues, we generated a transgenic mouse with overexpression of the mouse AGT gene restricted to the liver. The transgene was examined in two contrasted genetic backgrounds, the sodium-sensitive C57BL/6J and the sodium-resistant A/J. Transgenic and control male animals underwent continuous cardiovascular monitoring by telemetry for 14 days while under a standard sodium diet (0.2%). Moderate but significant increases in plasma AGT (40%, p = 0.01) and systolic blood pressure (4-6 mmHg, p ranging from 0.01 to <0.001) were observed in the sodium-sensitive background, but not in the sodium-resistant animals. Statistical analysis of a large number of consecutive, repeated measurements of blood pressure afforded power to detect small effects in the physiological range by use of advanced mixed models of analysis of variances and covariances. Although plasma renin activity was increased in the sodium-sensitive background, it did not reach statistical significance. These observations underline a potential contribution of systemic AGT to the mechanism of AGT-mediated hypertension, but the significance of sodium sensitivity in the genetic background suggests participation of the kidney in expression of the elevated blood pressure phenotype, a matter that will warrant further studies. They also highlight the challenge of identifying the contribution of individual genes in complex inheritance, as their effects are modulated by other genetic and environmental determinants.     

Angiotensinogen Gene M235T and T174M Polymorphisms and Susceptibility of Pre-Eclampsia: A Meta-Analysis

There are controversies in reports on the association of the angiotensinogen (AGT) gene polymorphisms with the risk of developing pre-eclampsia (PE). We performed a meta-analysis to examine the association between the AGT polymorphisms and PE risk: M235T (31 studies involving 2555 patients and 6114 controls) and T174M (six studies involving 681 patients and 2076 controls). For the M235T polymorphism, the TT genotype increased the PE risk as compared to the MM genotype (odds ratio 1.61, 95% confidence intervals 1.22-2.14, P= 0.001). When stratified by ethnicity, the TT genotype remained significantly associated with higher PE risk in Caucasians and Mongolians but not in Africans. Similar results were also obtained under all three genetic models of the M235T polymorphism. For the T174M polymorphism, no significant association was found in the comparisons (MT vs. TT and MM vs. TT) and under any genetic models. The analysis excluding the highly significant Hardy-Weinberg equilibrium-violating studies and sensitivity analysis further strengthened the validity of these associations. No publication bias was observed in this study. This meta-analysis demonstrates that the AGT M235T polymorphism is significantly associated with PE whereas the T174M polymorphism is not.     

AGT基因型对贝那普利降压疗效的影响

目的研究原发性高血压(EH)患者的血管紧张素原(AGT)基因M235T多态性与贝那普利降压疗效的相关性。方法251例EH患者口服贝那普利10～20mg/d,进行为期6周的降压治疗。用聚合酶链反应(PCR)和限制性酶切方法检测所有患者的AGT基因M235T多态性,按MM、MT和TT三种基因型分组。治疗前后及治疗过程中对患者的收缩压(SBP)和舒张压(DBP)等进行监测,以比较不同基因型患者之间的降压疗效。结果基因型为MM、MT及TT者分别为23例(9.2%)、104例(41.4%)和124例(49.4%);在251例患者中,MM、MT及TT三组患者间治疗后SBP和DBP的降幅差异无统计学意义(P>0.05);按年龄分层进行的亚组分析显示:在≥60岁的老年亚组中,治疗后MM、MT及TT三组患者DBP的降幅分别为(14.8±4.8)mmHg,(7.9±7.7)mmHg和(9.8±6.4)mmHg(P=0.034),MM较MT和TT组的DBP降幅大。结论本研究显示,老年(≥60岁)EH患者的AGTM235T多态性与贝那普利降压疗效相关,提示特定的基因多态性可能会影响某些降压药物的疗效。     

Association analyses of NsiI RFLP of human insulin receptor gene in hypertensives

Plasma angiotensinogen is elevated in essential hypertensives and shows a strong correlation with blood pressure. Patients with hypertension often display insulin resistance and we have found previously an association of a Rsal RFLP in intron 9 of the insulin receptor gene (INSR) with hypertension. Since insulin resistance is accompanied by hyperinsulinaemia and insulin can stimulate angiotensinogen production, we hypothesized that hypertension-associated genotypes of INSR may be associated with elevation in plasma angiotensinogen. We used PCR to detect a N sil RFLP in exon 8 of INSR and examined its relationship with plasma angiotensinogen, as well as hypertension, in 134 Caucasian hypertensives with two hypertensive parents and in 126 normotensives. Plasma angiotensinogen tracked weakly with the major allele of the N sil RFLP in hypertensives (p=0.08). Moreover, the frequency of this allele was higher in lean hypertensives than in lean normotensives (p<0.05) and in normolipidaemic hypertensives than normolipidaemic normotensives (p<0.02). The present study thus suggests that there could be a relationship of plasma angiotensinogen with INSR genotype, and of each with hypertension.     

Developmental stage-specific involvement of angiotensin in murine nephrogenesis

Angiotensinogen-deleted mice (Agt-KO) show phenotypes of hypotension and renal atrophy. To investigate whether an alternative pathway other than angiotensin II (AII), i.e., processed angiotensin fragments, may play a biological role in nephrogenesis, we analyzed a congenic line of Agt-KO fetuses and neonates derived from two sources: one (Agt-KO/He) from mating with heterozygous angiotensinogen-deleted mice and the other (Agt-KO/Ho) from mating homozygous angiotensinogen-deleted mice. Although Agt-KO/He did not show a typical phenotype at birth, these mice showed papillary atrophy 2 weeks later and thereafter, a marked increase in renal size, i.e., pelvic dilatation. In contrast, Agt-KO/Ho showed renal abnormalities at birth and subsequently died. TUNEL staining and electron microscopy revealed that accelerated papillary apoptosis was present at birth in Agt-KO/Ho and caused abnormal papillary development; however, apoptosis was not detected in Agt-KO/He, suggesting that different mechanisms for the abnormal renal development exist in Agt-KO/He and Agt-KO/Ho. Two-week administration of an angiotensin fragment (3–8), angiotensin IV (AIV), to Agt-KO/He markedly attenuated the renal atrophy, decreasing the incidence from 81% to 14%. However, administration of AIV to fetal Agt-KO/Ho through the mother did not decrease the incidence. This is marked contrast to AII, which prevented renal atrophy in both fetal and neonatal periods. It is therefore suggested that AIV is involved in nephrogenesis in a developmental stage-specific manner. Received: 2 September 1998 / Revised: 22 December 1998 / Accepted: 1 February 1999     

Polymorphism of the renin-angiotensin-aldosterone system in patients with chronic allograft dysfunction

Polymorphism of the gene encoding components of the renin-angiotensin-aldosterone synthase system (RAAS) represents an area of intense research of cardiovascular disease associations. Numerous studies have addressed the role of RAAS gene polymorphisms in the development and progression of renal disease. Also, it has been reported that patient with ACE (DD) and angiotensinogen AGT (TT) genotypes are associated with chronic allograft dysfunction (CAD). We investigated the effects of gene polymorphisms of the renin-angiotensin-aldosterone system in renal transplant patients (81 males and 50 females; mean age 29.6+/-10.2 years). Genotypes were determined using polymerase chain reaction sequence specific primers and PCR followed by RFLP analysis. Renal allograft recipients with chronic allograft dysfunction had significantly higher frequencies of the MM genotype than those without CAD (P<0.05). The other genetic polymorphisms of the RAAS were not associated with CAD. This study proves that determination of AGT M235T genotype before transplantation may help identify patients who are at risk for chronic renal transplant dysfunction.     

A comparison of the leech Theromyzon tessulatum angiotensin I-like molecule with forms of vertebrate angiotensinogens: a hormonal system conserved in the course of evolution

After five steps of purification including gel permeation, anti-angiotensin I affinity column chromatography followed by reverse-phase HPLC, a peptide immunoreactive to two different antisera (anti-angiotensin I) was purified to homogeneity from extracts of the leech Theromyzon tessulatum. The first 14 amino acid residues of the purified peptide (DRVYIHPFLLXWG) established by automated Edman degradation, reveal the existence in leeches of an angiotensin I-like molecule close to human angiotensin I. The sequence of the purified peptide presents 78.5% of homology with the N-terminal part of human angiotensin. Moreover, in its sequence, this peptide presents the cleavage sites of vertebrate angiotensin metabolic enzymes, i.e. the renin and the angiotensin-converting enzyme. This finding constitutes the first biochemical characterization of an angiotensin I in Invertebrates. It also reflects the high conservation of angiotensins in the course of evolution, suggesting a fundamental role of this family in fluid homeostasis.     

Association of angiotensinogen haplotypes with angiotensinogen levels but not with blood pressure or coronary artery disease: the Ludwigshafen Risk and Cardiovascular Health Study

Angiotensinogen and its cleaved forms angiotensin I and angiotensin II are important regulators of blood pressure. The gene for angiotensinogen (AGT) carries two common polymorphisms, T207M and M268T (previously described as T174M and M235T). To investigate the role of haplotypes formed by these polymorphisms for angiotensinogen levels we examined blood pressure, coronary artery disease (CAD), myocardial infarction (MI), and AGT genotypes and haplotypes in 2,575 patients with angiographically documented CAD and 731 individuals in whom CAD had been ruled out by angiography. Three haplotypes, designated as Hap1 (T207, M268), Hap2 (T207, T268) and Hap3 (M207, T268), accounted for more than 99% of alleles. The AGT Hap2 haplotype was significantly associated with angiotensinogen levels; one additional Hap2 allele accounted for an approx. 8% increase in angiotensinogen. This association was stronger than that of either single polymorphism. AGT genotypes or haplotypes were not related to hypertension, CAD or MI. We conclude that a common haplotype of the angiotensinogen gene is linked to angiotensinogen levels but has no major impact on blood pressure, hypertension, or cardiovascular risk.