AGT基因M235T变异与腰臀比异常对原发性高血压的影响

目的探讨AGT基因第二外显子编码M235T变异与腰臀比异常及其交互作用对原发性高血压的影响。方法对从青岛市4个社区中筛检出的、未经药物系统治疗的235例原发性高血压病人及240例正常血压者进行调查,用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测M235T变异;应用相加模型分析M235T变异与腰臀比异常的交互作用。结果高血压组T等位基因频率(46.81%)及腰臀比异常率(69.79%)高于对照组(分别为37.71%,47.92%),差别有统计学意义(χ2=8.677,23.433,P0.01)。AGT基因M235变异与腰臀比异常具有正交互作用。用多因素分析调整年龄、性别、体质指数、饮酒、吸烟、血脂等因素后,M235T基因变异与腰臀比异常的协同效应指数(S)为1.945,归因交互效应(AB)为1.022,归因交互效应百分比(AP%)为32.91%,纯因子间AP为48.55%。结论 AGT基因第二外显子编码M235T变异与原发性高血压有关,AGT基因M235T变异与腰臀比异常具有正交互作用,控制腰臀比异常可以降低居民原发性高血压患病的危险性。     

Genetic polymorphisms in vasoactive genes and preeclampsia: a meta-analysis

There are controversies in reports on the association of polymorphisms in endothelial nitric oxide synthase, angiotensinogen, angiotensin receptor type 1 and angiotensin-converting enzyme genes with an increased risk of developing preeclampsia. We performed a systematic search of published case-control studies through the PubMed database up to January 2006, and report the results of a meta-analysis of polymorphisms investigated in more than five studies: Glu298Asp in eNOS gene (9 analyses involving 1055 patients and 1788 controls), Met235Thr in AGT gene (13 analyses involving 1128 patients and 2278 controls), and intron 16 insertion-deletion polymorphism in ACE gene (10 analyses involving 1121 patients and 1361 controls). Statistically significant associations with preeclampsia were identified for the Met235Thr/AGT polymorphism: OR 1.65 (95% CI 1.19, 2.29) if the polymorphism is considered under the dominant genetic model, and OR 1.54 (95% CI 1.12, 2.11) under the recessive model. For insertion-deletion/ACE polymorphism, statistical significance was demonstrated when the polymorphism was considered under the recessive model: OR 1.51 (95% CI 1.17, 1.94). No single polymorphism was identified as having a major effect.     

载脂蛋白B、载脂蛋白E及血管紧张素原基因多态性与冠心病的关系

目的探讨载脂蛋白B、E（ApoB、ApoE）基因及血管紧张素原基因（AGT）多态性与冠心病（CHD）的相关性。方法采用基因芯片技术分析89例CHD患者和78例非CHD患者的ApoBXbaI、ApoEl12／158及AGTM235T基因多态性及等位基因频率。结果CHD组ApoBXbaI、ApoEl12／158及AGTM235T基因型分布与对照组相比差异有统计学意义（P〈0．05）。CHD组的Apo BXba I的X^＋ X^＋基因型及等位基因X’频率显著高于对照组,差异有统计学意义（P〈0．05）,ApoE112／158的ε^4/、ε^4/4基因型及等位基因￡。频率高于对照组,差异有统计学意义（P〈O．05）;CHD组AGT—TT基因型频率及T等位基因频率均明显高于对照组,差异有统计学意义（P〈0．05）。结论ApoBXbaI、ApoEll2／158和AGTM235T的基因多态性可能是中国人CHD的危险因素。ApoB Xba I等位基因X^＋;ApoE112／158的等位基因ε^4和AGT M235T基因的T等位基因是CHD的重要遗传标记。     

米索前列醇预防AGT基因多态性产妇产后出血的临床研究

目的:研究米索前列醇防治AGT基因多态性产妇产后出血的临床疗效。方法:选择具有AGT M235T基因多态性患者80例,均行剖宫产手术,按照基因型随机分为观察组40例和对照组40例,分别给予米索前列醇400μg(直肠给药)和宫体注射催产素20 U,观察产妇AGT基因多态子痫前期的发生率,用药后产后出血情况及血压变化情况。结果:①观察组及对照组中具有TT基因型产妇子痫前期发生率明显高于具有MM型及MT型产妇;②观察组产后2 h内各基因型出血量明显少于对照组,出血量比较有差异,TT型出血量比较有统计学差异;2~24 h内出血量,观察组较对照组少,但无统计学差异;③两组产妇术后血压均较前明显下降,但两组间差异无统计学意义。结论:携带有AGT基因TT型的妇女子痫前期发病危险度升高;米索前列醇用于防治子痫前期产妇产后出血方便、安全、而对围产期母儿的健康无不良影响。     

血管紧张素原基因M235T和T174M多态性与新疆哈萨克族高血压左室肥厚的关系

目的:探讨新疆哈萨克族原发性高血压(EH)人群中血管紧张素原(AGT)基因M235T和T174M多态性的分布及其与EH伴左室肥厚(LVH)的关系。方法:对86例心电图诊断的EH伴LVH患者(LVH组)与95例不伴LVH患者(NLVH组)进行病例-对照研究,即记录标准12导联以传统的电压诊断标准与Romhilt计分系统积分作为诊断LVH的指标。采用聚合酶链式反应(PCR)与限制性片段长度多态性(RFLP)技术检测AGT基因M235T变异及T174M变异。结果:①M235T基因型有2种形式,T174M基因型有3种形式;2组AGT基因型的分布均符合Hardy-Weinberg平衡;②AGT基因M235T和T174M基因型及等位基因在LVH组与NLVH组的分布均差异无统计学意义(均P>0·05);③按性别分层,M235T基因型和等位基因频率在2组男女之间均差异无统计学意义(均P>0·05);T174M基因型和等位基因频率在LVH组男女之间亦均差异无统计学意义(均P>0·05),而在NLVH组男女之间差异有统计学意义(均P<0·05);④AGT基因M235T,T174M位点不同组合基因型在2组人群的构成不存在显著性差异(P>0·05)。结论:AGT基因M235T及T174M多态性与新疆哈萨克族EH伴LVH的发生无相关性。AGT基因M235T及T174M多态性可能不是新疆哈萨克族EH伴LVH的遗传危险因素。     

On the plasticity of the cerebellar renin-angiotensin system: localization of components and effects of mechanical perturbation

This study focuses on the renin-angiotensin system (RAS) in the cerebellar cortex and changes within this system after mechanically induced cerebellar injury. Using radioactive and non-radioactive in situ hybridization and immunocytochemistry angiotensinogen mRNA, angiotensinogen, angiotensin II and, for the first time, N-terminal angiotensin fragment (1–7) immunoreactivities, respectively, were demonstrated in the rat cerebellum. Angiotensinogen mRNA and angiotensinogen immunoreactivity (IR) were both present in glial cell populations of all layers, especially in the Purkinje and granular cell layers and within the cerebellar nuclei. Angiotensin II IR was demonstrated in glial cell population in all layers using a monoclonal angiotensin II antibody, while with a polyclonal angiotensin II antiserum (Denise) some Purkinje cell bodies were labelled. After lesioning the cerebellar cortex mechanically by an injection cannula a strong increase in angiotensinogen gene expression as well as in angiotensin II and angiotensin (1–7) immunoreactivities were observed in the glial cell populations. Furthermore, putative Bergmann glial processes, as indicated from the morphological appearance became strongly angiotensin II and angiotensinogen immunoreactive in the region close to the mechanically induced lesion. It could inter alia be demonstrated for the first time using confocal laser microscopy of ANG II IR and GFAP IR that ANG II in vivo in the intact cerebellar cortex is present in astroglial processes in the molecular layer and presumably secreted into the extracellular space in form of small spheric bodies and/or taken up by other cell types. In contrast, the N-terminal fragment angiotensin (1–7) IR was restricted to the glial cell populations and appeared only after the lesion event. Thus, it is suggested that the cerebellar RAS shows marked changes in response to mechanically induced lesions. The expression of angiotensinogen as well as the production of angiotensinogen IR and angiotensin II like IR is even after mechanical lesion restricted to astrocytes, i.e., cerebellar astrocytes and putataive Bergmann glial cells, and in case of immunoreactivities it spreads to the radially oriented Bergmann glial processes in the molecular layer.     

肥厚型心肌病患者血管紧张素原M235T基因多态性研究

目的 :探讨中国人群血管紧张素原 (AGT)基因多态性与肥厚型心肌病 (HCM )发病的关系。方法 :应用PCR技术扩增AGT基因目的片断 ,检测基因多态性。结果 :HCM患者的AGTT等位基因频率高于对照组(P <0 .0 5 ) ,HCM患者中同时具有AGTT等位基因和血管紧张素转换酶 (ACE)缺失 (D)等位基因及AGTTT ACEDD基因型者明显高于对照组 (P <0 .0 1,P <0 .0 5 ) ,DD TT基因型的HCM患者心脏事件发生率高于其它基因型组合者和AGTTT型者 (P <0 .0 1,P <0 .0 1)。结论 :AGTT等位基因是HCM的危险因素 ,AGTT和ACED等位基因及TT和DD基因型对HCM发病具有协同作用 ,具有ACEDD AGTTT基因型的HCM患者有较严重的临床表型。     

Intrarenal angiotensinogen: localization and regulation

Multiple lines of evidence (physiologic, immunohistochemical, and molecular biologic) support the presence of a complete intrarenal renin-angiotensin system (RAS). Localization of angiotensinogen messenger ribonucleic acid (mRNA) within the proximal tubule, together with demonstration of renin and converting enzyme mRNAs within the kidney, provide the most persuasive evidence for local, independent synthesis. Data from a combination of in situ hybridization studies, Northern analysis, and physiologic manipulations lead us to propose that a major site for action of a local RAS is the proximal tubule. There, locally generated angiotensins may regulate sodium reabsorption and urine pH. A variety of factors appear to regulate renal angiotensinogen. For instance sodium depletion increases the expression of renal angiotensinogen (as well as renin mRNA), as does high potassium intake and androgen administration. In pathologic states, such as experimental heart failure, and certain models of hypertension, such as the spontaneously hypertensive rat, expression of renal angiotensinogen mRNA levels is altered. It is proposed that changes in the intrarenal RAS may play a role in the maintenance of homeostasis and in the pathophysiology of various disease states.     

The thrifty-genotype hypothesis and its implications for the study of complex genetic disorders in man

 According to the ”thrifty-genotype” hypothesis proposed by Neel, diseases of civilization such as non-insulin-dependent diabetes mellitus and hypertension result from a discordance between certain features of our present-day environment and our genetic make-up which evolved to fit the life of Paleolithic humans. This concept implies that while ”affected” individuals harbor the ”original” ancestral version of the relevant genes, healthy or ”unaffected” individuals have picked up recent mutations leading to a ”loss of thriftiness” of these genes. Support for this concept now comes from recent studies of the angiotensinogen gene, where an ancestral variant of the gene (AGT 235T), also present in primates, has now been associated with hypertension whereas a neomorphic variant (AGT 235M) apparently reduces the risk of high blood pressure. The implications of these findings for our understanding and approach to the study of complex genetic diseases is discussed. Received: 9 July 1997 / Accepted: 5 November 1997     

Angiotensinogen and Kininogen: Cloning and Sequence Analysis of the Cdnas

The primary structures of the angiotensinogen precursor and the low molecular weight (LMW) kininogen precursors have been deduced by determining the nucleotide sequences of cloned DNAs complementary to their mRNAs. The angiotensinogen precursor consists of a mature angiotensinogen of 453 amino acid residues and a putative signal peptide of 24 amino acid residues. An angiotensin moiety is located at the amino-terminal part of angiotensinogen, preceded directly by the signal peptide and followed by a large carboxyI-terminal sequence that contains two internally homologous sequences and three potential glycosylation sites. The LMW kininogen precursors are encoded by two very similar but distinct mRNAs and composed of 436 and 434 amino acid residues. Both kininogens contain two internally homologous sequences in which all amino acid differences between the two kininogens are located. This suggests that these homologous regions may be biologically significant in relation to the existence of two LMW kininogens.