Angiotensinogen as a risk factor for essential hypertension in Japan.

A common molecular variant of angiotensinogen (AGT), the precursor of the potent vasoactive hormone angiotensin II, has been incriminated as a marker for a genetic predisposition to essential hypertension in Caucasians (Jeunemaitre, X., F. Soubrier, Y. V. Kotelevtsev, R. P. Lifton, C. S. Williams, A. Charru, S. C. Hunt, P. N. Hopkins, R. R. Williams, J. M. Lalouel, and P. Corvol. 1992. Cell. 71:169-180). We now show that the same variant, T235, is associated with essential hypertension in Japanese patients. The observation of this association in a distinct, ethnically homogeneous population further substantiates an involvement of angiotensinogen in the pathogenesis of essential hypertension and has physiological, epidemiological, and evolutionary implications.     

Angiotensinogen gene is expressed and differentially regulated in multiple tissues of the rat.

To define the role of local synthesis of angiotensinogen in tissue angiotensin production, we have quantitated angiotensinogen messenger RNA (mRNA) levels in 17 different tissues of four groups of rats: control rats, nephrectomized rats, rats given dexamethasone, ethynylestradiol, and triiodothyronine, and nephrectomized rats given dexamethasone, ethynylestradiol, and triiodothyronine. Angiotensinogen mRNA was identified in 12 tissues: liver, kidney, brain, spinal cord, aorta, mesentery, atria, lung, adrenal, large intestine, stomach, and spleen. Angiotensinogen mRNA was not identified in pituitary, ventricle, testis, small intestine, or pancreas. When expressed per gram tissue wet weight, angiotensinogen mRNA levels of extrahepatic tissues were less than 4% of hepatic levels. However, when expressed per milligram total RNA, angiotensinogen mRNA levels of brain, spinal cord, aorta, and mesentery were 26-42% of hepatic levels. Regulation of angiotensinogen mRNA levels was tissue specific. This demonstration of a widespread tissue distribution of angiotensinogen mRNA may indicate a similarly widespread distribution of local angiotensin systems that are independent of the circulating renin-angiotensin system.     

Angiotensinogen in chronic liver disease.

The renin substrate angiotensinogen (AGT) belongs to a supergene family of proteins that also includes alpha 1-antitrypsin (AAT) and alpha 1-antichymotrypsin (ACT), acute-phase reactants with known serine proteinase inhibitory (serpin) function. AGT lacks a known inhibitory function but is an acute-phase reactant. In this study we have compared the plasma levels, as analysed by electroimmunoassay, of AGT with AAT in patients with different types of chronic liver disease. AAT levels are regularly elevated in liver disease patients in contrast to AGT, which remains normal until late in the disease course. The AGT levels (mean +/- SD) were: in alcoholic cirrhosis (n = 19) 100 +/- 27.3%, in chronic active hepatitis (n = 14) 100 +/- 23.2%, in primary biliary cirrhosis (n = 18) 106 +/- 26.1% and in non-alcoholic cirrhosis (n = 15) 92 +/- 38.4%. Only occasionally were levels less than 50% of normal seen. In general, AGT levels were unrelated to sex and type of underlying liver disease and did not correlate with degree of hepatocellular impairment. Crossed immunoelectrophoresis showed no abnormal charge heterogeneity of AGT in patients with low levels. Our data are consistent with a dissociate expression of the homologous serpin genes in chronic liver disease. We speculate that the magnitude of the dissociated response is influenced by hormonal factors.     

心肌梗死患者血管紧张素原基因T174突变检测的临床意义

目的探讨血管紧张素原基因(AGT)T174在人群中的分布、与临床心肌梗死的相关性。方法对入选的心肌梗死患者组及健康对照组,用聚合酶链反应(PCR)、限制性片段长度多态性(RFLP)分析,对群体患者和群体健康对照组进行基因分型,统计分析。结果 AGT基因型频率及等位基因频率分布比较均匀;心肌梗死发生与民族、性别、年龄无特异相关性。174MM型和M 174等位基因的频率患者组显著高于健康对照组,携带突变型MM基因型的个体比野生型TT者患心肌梗死的危险性高5.667倍,基因突变与心肌梗死发生相关。结论 AGT基因基因型及等位基因在群体中的分布无民族、年龄、性别差异,MM基因型与心肌梗死有关。     

Angiotensinogen gene M235T polymorphism and reduction in wall thickness in response to antihypertensive treatment

The angiotensinogen M235T polymorphism has been linked to hypertension and cardiovascular disease. Carotid intima-media thickness (IMT) is an early marker of atherosclerosis. The objectives of the present study were to determine in previously untreated essential hypertensive patients whether carotid IMT was associated with the M235T polymorphism, and to determine whether the M235T polymorphism could influence the reduction of carotid IMT by antihypertensive treatment. Common carotid artery IMT was determined with a high-definition echotracking system in 98 previously untreated hypertensive patients in a cross-sectional study. A subgroup of 56 patients was included in a randomized double-blind parallel group study comparing the effect of the angiotensin-converting-enzyme-inhibitor enalapril with that of the beta-blocker celiprolol during a 5 month period. In the cross-sectional study, a multivariate analysis showed that the M235T genotype was a significant independent determinant of carotid IMT, explaining 7% of the variance. Carotid IMT was higher in patients homozygous for the T allele than in MM patients. In the longitudinal study, the reduction in carotid IMT after antihypertensive treatment was significantly ( P <0.01) higher in patients carrying the TT genotype than in patients carrying the MM genotype, despite similar reductions in blood pressure and independently of drug type. In conclusion, these data suggest that the angiotensinogen TT genotype at position 235 is a genetic marker for early carotid atherosclerosis in a hypertensive population and its regression under antihypertensive treatment.     

Angiotensinogen M235T gene polymorphism and recurrent restenosis after repeated percutaneous transluminal coronary angiography

The present study was designed to prospectively test the hypothesis that gene polymorphisms of the renin-angiotensin system are associated with recurrent restenosis after repeated percutaneous transluminal coronary angioplasty. Five hundred and eleven patients after first successful angioplasty were characterized with respect to the angiotensinogen M235T, angiotensin-converting enzyme insertion/deletion and angiotensin II type 1 receptor A1166C gene polymorphisms. In 164 of these patients repeated angioplasty on a restenotic lesion was performed. After repeated angioplasty, 46 patients had recurrent restenosis as defined by a greater than 50% progression of residual stenosis. In the recurrent restenosis group there was a statistically significant higher percentage of patients receiving cholesterol-lowering drugs compared with the group of patients without recurrent restenosis. The two groups of patients did not differ with respect to procedural and angiographic parameters. There were significantly more carriers of the angiotensinogen 235T allele in the recurrent restenosis group than in the control group without recurrent restenosis. No differences between the two groups were found with respect to the other gene polymorphisms investigated. According to the results of a multifactorial analysis of variance, only the 235T allele of the angiotensinogen gene and not cholesterol drug therapy independently affected the increase of stenosis at follow-up angiography. In conclusion, the angiotensinogen 235T allele may be an independent predictor for recurrent restenosis after repeated angioplasty.     

Haplotype-based case-control study of the human AGTR1 gene and essential hypertension in Han Chinese subjects

ObjectivesEssential hypertension is considered to be a multifactorial trait resulting from the combined influence of environmental and genetic determinants. The aim of the study is to assess the association between the human AGTR1 gene and essential hypertension (EH) using a haplotype-based case-control study in Han Chinese subjects.Design and methodsSeven tag SNPs and the A1166C polymorphism of the AGTR1 gene were genotyped in 510 hypertension subjects and 510 normotensive subjects using PCR-RFLP method.ResultsSingle SNP analyses indicated that the rs12695895 was significantly associated with hypertension, adjusted for covariates. Compared with the other haplotypes, Hap4 (AGGACTT) which carry the susceptible rs12695895 A allele was found to significantly increase the risk of EH with odds ratios equal to 1.84 (p = 0.0002).ConclusionsThe present results indicate that rs12695895 might be a genetic marker for EH and Hap4 (AGGACTT) was associated with hypertension in Han Chinese population.     

心肌梗死患者血管紧张素原基因多态性临床检测意义的研究

目的 探讨血管紧张素原基因（AGT）在人群中的分布、临床常见生化指标与心肌梗死的关系。方法 选取患者组114例及对照组204例，用聚合酶链反应（PCR）、限制性片段长度多态性（RFLP）分析，对群体患者和群体健康对照组进行基因分型，统计分析。结果 ACT基因型频率及等位基因频率分布比较均匀；心肌梗死发生与性别、年龄无特异相关性。174MM型和M174等位基因的频率患者组显著高于健康对照组，携带突变型MM基因型的个体比野生型TT者患心肌梗死的危险性高5．667倍，基因突变与心肌梗死发生相关。其他因素中只有吸烟与否其P值〈0．001。校正主要危险因素后，MM基因型仍与心肌梗死发病显著相关，调整后P值分别为0．043和0．001。结论 AGT基因基因型及等位基因在群体中的分布无年龄、性别差异，MM基因型与心肌梗死有关。     

Angiotensinogen is an acute-phase protein in man

Accumulating information concerning the structure of angiotensinogen suggests a resemblance of this component of the renin-angiotensin system to the acute-phase protein alpha 1-antitrypsin. Compared to a group of age- and sex-matched controls without signs of infection, markedly elevated levels of angiotensinogen (increase in median value: 70%), alpha 1-antitrypsin (102%), caeruloplasmin (76%), haptoglobin (261%), and orosomucoid (162%) were found in plasma from 14 patients with acute inflammatory disease. This finding indicates that angiotensinogen should be included in the list of acute-phase proteins in man, and raises the question whether angiotensinogen is involved in the regulation of the renin-angiotensin system during inflammation and tissue injury.     

β肾上腺素能受体基因多态性与原发性高血压的关系

目的:β肾上腺素能受体包括β1,β2和β3三种亚型,分析其基因多态性与原发性高血压的关系。方法:试验于2003-02/2005-09在重庆医科大学生物医学工程研究室进行。选择在清华大学第一附属医院和重庆医科大学第二附属医院就诊和体检的150例原发性高血压患者,男80例,女70例,年龄(56.53±5.60)岁;130例正常对照者,男70例,女60例,年龄(55.62±8.63)岁,对试验均知情同意。测试受试者坐位血压。用聚合酶链反应-限制性片段长度多态性技术和等位基因特异性聚合酶链反应法分析β1-肾上腺素能受体的Ser49Gly和Arg389Gly,β2-肾上腺素能受体的Arg16Gly和Gln27Glu,β3-肾上腺素能受体的Trp64Arg基因多态性,并分析其基因多态性与原发性高血压的相关性。结果:①β1-389原发性高血压组和对照组的Arg/Arg,Arg/Gly和Gly/Gly基因型频率分别为:0.56,0.32,0.12和0.74,0.22,0.04(P<0.05),Arg和Gly的等位基因频率在原发性高血压组和对照组分别为0.72,0.28和0.85,0.15,两组间差异显著(P<0.05)(OR=0.45,95%可信区间:0.30-0.69)。②β2-16原发性高血压组和对照组的Arg/Arg,Arg/Gly和Gly/Gly基因型频率分别为:0.17,0.67,0.16和0.27,0.69,0.04(P<0.05)。Arg和Gly的等位基因频率在原发性高血压组和对照组分别为0.51,0.49和0.62,0.38,两组间差异显著(P<0.05)(OR=0.64,95%可信区间:0.46～0.90)。③β1-肾上腺素能受体的Ser49Gly,β2-肾上腺素能受体的Gln27Glu,β3-肾上腺素能受体的Trp64Arg的基因型频率和等位基因频率在原发性高血压组和对照组之间差异无显著性(P>0.05)。所有组的基因多态性分布均符合Hardy-Weinberg定律。结论:在所研究的中国人群中,β1-389Arg/Gly和β2-16Arg/Gly基因多态性与原发性高血压的发病有联系。     

醛固酮合成酶CYP11B2基因多态性与中国汉族人原发性高血压关系的系统分析

目的 Meta分析中国汉族人醛固酮合成酶CYP11B2基因多态性与原发性高血压关系。方法 查阅1980年1月至2006年7月发表的有关醛固酮合成酶CYP11B2基因多态性与原发性高血压关系的病例对照试验研究文献，选择的数据库有中国生物医学文献数据库（CBMdise）、中国学术期刊全文数据库（CAJ—CD）和Medline。以原发性高血压组和健康对照组基因分布的OR值为统计量，全面检索相关文献并剔除不符合要求的文献，排除发表偏倚的影响。应用RevMan4．2软件对各研究结果进行一致性检验和数据合并。最终入选5篇随机对照试验文献。结果 5．篇文献的病例对照试验一致性较好，原发性高血压组总计高血压患者1000例，对照组967例，原发性高血压组与对照组TT/（TC＋CC）OR值（95％可信区间）0．95（0．79，1．13），显著性检验Z值为0．60，P=0．55。T等住基因频率OR值为（95％可信区间）0．92（0．80，1．06），显著性检验Z值为1．17，P=0．24。结论 中国汉族人醛固酮合成酶CYP11B2基因多态性与原发性高血压无关。     

肾素基因启动子区单倍型与原发性高血压的关系

目的:在中国华东地区汉族人群中检测肾素基因启动子区的单核苷酸多态(SNPs)及单倍型分布,并探讨其与原发性高血压的关系。方法:应用聚合酶链反应(PCR)直接测序技术检测肾素基因启动子区以明确其SNPs分布。在192例原发性高血压患者(原发性高血压组)及185例健康对照者(对照组)中对所发现的SNPs开展病例-对照关联研究及基因单倍型分析。结果:所测肾素基因启动子区长度为1674bp,共发现5个SNPs,其中RENP/-1475(G/A)、RENP/-1447(T/G)、RENP/-1165(G/A)和RENP/-1135(T/G)几乎呈完全的连锁不平衡。RENP/-1475(G/A)和RENP/-1292(A/G)多态的基因型和等位基因分布在原发性高血压组与对照组之间差异无统计学意义(P>0.05)。被检出的5个SNPs属同一单倍域,产生3种单倍型,各单倍型在原发性高血压组和对照组的分布频率差异亦无统计学意义(P>0.05)。结论:肾素基因启动子区遗传变异可能并不是中国华东地区汉族人群原发性高血压的易感因素。     

Link between hypertension and diabetes mellitus epidemiological study of Chinese adults in Taiwan.

OBJECTIVE: To elucidate the relationship between hypertension and non-insulin-dependent diabetes. RESEARCH DESIGN AND METHODS: The study consisted of a random sample of adults aged greater than or equal to 40 yr from the Ta-An district of Taipei City and 5 of 12 villages of Taiwan province, which had established primary health-care centers since 1984. A total of 11,478 subjects were recruited into the survey with a response rate of 65.3 and 72%, respectively. Blood glucose and blood pressure levels were measured, and a structured questionnaire was given to each participant. Those identified as having diabetes received further blood tests for lipids and creatinine and were evaluated for vascular complications. RESULTS: The age- and sex-adjusted prevalence of hypertension among diabetic subjects was twice that of nondiabetic subjects (30.6 vs. 16.4%, P less than 0.0005). Hypertensive subjects had a higher prevalence of diabetes than normotensive subjects (10.2 vs. 4.9%, P less than 0.0005). Among hypertensive subjects, the prevalence of diabetes was 12.7% for those taking antihypertensive drugs and 9.1% for those not taking any drug (P less than 0.05). The prevalence of diabetes significantly increased as mean arterial pressure rose, whether the subjects were stratified by various factors. Multiple regression analysis, including sex, age, body mass index, and other risk factors as independent variables, also showed a significant association between diabetes and hypertension. CONCLUSIONS: The univariate and multivariate analyses revealed that there seemed to be a tight link between hypertension and non-insulin-dependent diabetes. Family history of diabetes, diabetes duration, diabetes regimen, control of blood glucose, and the presence of nephropathy, as attested by proteinuria, did not contribute to the risk of hypertension. Further studies are necessary to determine whether these two conditions are causally related.