肾素-血管紧张素基因多态性与左心室质量构象及功能相关性的研究现状

肾 素 血管紧张素系统 (RAS)在高血压及其他心血管疾病的发生发展中起重要的作用。人类血管紧张素转换酶、血管紧张素原、血管紧张素Ⅱ一型受体基因染色体定位以及克隆成功 ,为其在心血管疾病病因学研究确立了分子生物学基础。目前高血压病研究的三大前沿领域包括 :寻找新的导致高血压病基因 ;阐明导致高血压靶器官损伤的基因易感性 ;抗高血压药物的药物基因学。高血压病被认为是一种多基因遗传病 ,同时与环境因素关联。基因在高血压相关的靶器官疾病的发生发展中的作用效应 ,可能由以下三个途径完成。 ( 1)基因不直接影响血压变化 ,但是…     

MS-PCR法重新评估血管紧张素原基因M235T多态性与家族性原发性高血压的相关性

多种心血管疾病与肾素 -血管紧张素系统 (renin-angiotensin system,RAS)密切相关。目前研究较多的肾素 -血管紧张素系统候选基因如血管紧张素转化酶 (angiotensinconverting enzyme,ACE)和血管紧张素原 (angiotensinogen,AGT)基因、尤其是 AGT基因与心血管疾病的关系日益受到重视。 1992年 Jeunemaitre等 [1 ]应用同胞对 (sib- pair)分析发现 ,AGT基因中微卫星多态性与高血压发生相关 ,随后又陆续在 AGT基因编码区找到多个突变位点。其中外显子 2区域核苷酸 70 4处胸腺嘧啶 (T)被胞嘧啶 (C)替代 ,导致基因编码产物第 2 35号氨基酸…     

血管紧张素受体拮抗药洛沙坦研究进展

洛沙坦 (L osartan)是 1994年经美国食品与药物管理局(FDA)批准上市的新一代降压约。它是血管紧张素 (Angiotensin ,Ang )受体的拮抗药 ,在降压、抗心衰等方面有独特的疗效。近年来 ,血管紧张素 受体拮抗药(Angiotensin receptor antagonist,A- - A)的研究颇多 ,现将洛沙坦的进展概述如下。1　血管紧张素 受体拮抗药的开发与应用血管紧张素 (Ang )是肾素 -血管紧张素 -醛固酮系统 (RAS)的主要活性介质 ,在高血压发病及其靶器官损害中产生重要的病理生理作用 ,因而使阻断 RAS达到治疗高血压的目的成为可能〔1〕。一方面干预 Ang …     

肾素血管紧张素系统3个关键基因多态性与原发性高血压关系研究进展

目的 综述肾素血管紧张素系统3个关键基因即血管紧张素原、血管紧张素转换酶及血管紧张素(Ⅱ)-1型受体基因多态性与原发性高血压关系的研究进展.方法 从血管紧张素原,血管紧张素转换酶及血管紧张素(Ⅱ)-1型受体基因的生物学特征及与原发性高血压关系的实验研究结果两方面进行分析.结果 血管紧张素原、血管紧张素转换酶及血管紧张(Ⅱ)-1型受体是原发性高血压发病的热点基因.结论 血管紧张素素原、血管紧张素转换酶及血管紧张素(Ⅱ)-1型受体基因多态性与原发性高血压关系的研究结果有助于揭示原发性高血压的发病机制,指导临床用药和基因治疗.     

血管紧张素转换酶基因多态性与原发性高血压左室肥厚的关系

血管紧张素转换酶 (ACE)是肾素—血管紧张素系统 (RAS)的重要酶 ,在心血管疾病发生中起重要作用。作为心血管疾病的重要候选基因的 ACE基因与原发性高血压、左室肥厚等心血管疾病之间的关系受到国内外广泛关注。在此基础上 ,近几年国内外学者因应用扩增片段长度多态性分析等分子生物学技术就ACE基因与左室肥厚的关系进行了病例—对照研究 ,结果显示 ACE基因与左室肥厚间存在联系 ,认为 ACE基因是高血压左室肥厚的重要遗传因素 ,为指导用药及高血压并发症预防提供新的启示。     

脑室注入血管紧张素Ⅱ对大鼠组织和血浆环核苷酸及血浆血管紧张素Ⅱ水平的影响

肾素-血管紧张素系统(RAS)在血压调节和高血压发病中具有重要作用。而RAS本身也受到中枢神经系统的调制及多种体液因素的影响。研究证明脑内存在有血管紧张素Ⅱ受体(ANGⅡR)激活ANGⅡ可以引起血压升高等一系列变化。在肾性高血压大鼠我们曾观察到中枢和外周的环核苷酸浓度的     

肾素-血管紧张素系统基因多态性与2型糖尿病脑梗塞的关系

目的研究肾素-血管紧张素系统(renin-angiotensin system,RAS)中血管紧张素Ⅱ的1型受体(type1angiotensin Ⅱ receptor,AT1R)基因A1166C多态及血管紧张素Ⅰ转化酶(angiotensin1-converting enzyme,ACE)基因插入/缺失(I/D)多态与中国汉族2型糖尿病(type 2 diabetes     

中枢神经系统疾病中AT_1受体作用的研究进展

<正>肾素血管紧张素系统(rennin-angiotensin system,RAS)是体内重要的体液调节系统,参与全身及局部血管、水及电解质的调节。另外在血管壁、心脏、中枢神经、肾脏及肾上腺等组织中也存在RAS各成分。近年来发现外周及脑内RAS参与中枢神经系统有关疾病的发生发展。其中血管紧张素Ⅱ(angiotensin,AngII)是RAS的主要活性物质,血管紧张素I型(angiotensin type 1,AT1)受体是AngII生物学效应的主要介导受体。本文主要对AT1受体在中枢神经系统疾病中的     

血管紧张素受体的研究进展

血管紧张素Ⅱ受体(ATR)是机体肾素-血管紧张素系统(RAS)的重要组成成分之一,介导血管紧张素Ⅱ的生理学效应,参与血管舒缩、水盐代谢和醛固酮分泌以及血管平滑肌增生和功能调节等,是RAS系统作用于效应器的关键步骤。本文对ATR分型、生物学效应、基因表达调控及其信号转导途径进行综述。     

血管紧张素Ⅱ及其受体在脑血管疾病中作用研究进展

<正>肾素-血管紧张素系统(renin angiotensin system,RAS)是一个重要的水电解质平衡调节系统。近年来,研究发现脑内存在独立的RAS[1],与循环系统RAS共同参与了脑结构与功能的调节。血管紧张素II(angiotensin Ⅱ,Ang Ⅱ)是RAS中的主要生物活性成分,在脑血管生理学和病理生理学的作     

Polymorphism in angiotensin II receptor genes and hypertension

Molecular variants of individual components of the renin-angiotensin system (RAS) have been thought to contribute to an inherited predisposition towards essential hypertension. The angiotensin II type 1 receptor (AT-1) mediates the major pressor and trophic actions of angiotensin II (Ang II) and at least 50 different polymorphisms have been described in the AT-1 gene (AT(1)R gene); in particular, the C allele of the +1166A/C polymorphism has been associated with the severe form of essential hypertension, but the role of this polymorphism is still ambiguous in pathologies related to high Ang II levels, such as deterioration of renal function, arterial stiffness and hypertrophic cardiomyopathy. A relationship was suggested between AT 1R A1166C polymorphism and the humoral and renal haemodynamic responses to losartan, an AT-1 blocker, as well as with enhanced Ang II vascular reactivity or sensitivity. Polymorphism has also been described in angiotensin II type 2 receptor (AT-2) gene, AT-2 being the mediator for vasodilatation, natriuresis and apoptosis of smooth muscle cells; associations were found between some of these polymorphisms and both hypertension and left ventricular structure. Further evaluation in adequately powered studies is necessary for full assessment of the allelic markers in genes for RAS components, as well as to allow determination of a predisposition to hypertension or related diseases and selection of an appropriate antihypertensive drug for an individual.     

Gene-gene interaction in the RAS system in the predisposition to myocardial infarction in elder population of St. Petersburg (Russia)

The aim of this study was to estimate the frequencies of some DNA polymorphisms of two genes of the renin-angiotensin system (RAS), M235T angiotensinogen gene and insertion-deletion polymorphism in angiotensin-converting enzyme gene, in older (>55 years old) myocardial infarction survival and control groups. For this purpose 198 myocardial infarction (MI) patients and 152 randomly selected healthy persons have been analyzed. We have not found any differences in allele and genotype distribution in the above-mentioned genes for either group. However, statistical research showed a significant increase of double homozygotes IITT in the group of MI patients as compared with those in the control group. In this respect we suggested that gene-gene interaction in the RAS system may be considered to be a predisposing factor for MI development.     

IL-1B and IL-6 gene polymorphisms encode significant risk for the development of recurrent aphthous stomatitis (RAS)

Recurrent aphthous stomatitis (RAS) is an, ulcerative condition of the mouth, with a polygenic mode of inheritance in which cytokines are thought to play an important role. Ninety-one RAS patients and 91 controls were genotyped for known IL-1A, IL-1B, IL-1RN and IL-6 gene polymorphisms. Inheritance of the G allele of the IL-1B -511 polymorphism was strongly associated with RAS (OR = 2.5, P < 0.00002), with increased numbers of G/G homozygotes (OR = 4.5, P < 0.0005). The G allele of IL-6 -174 also occurred more frequently in RAS (OR = 2.6, P < 0.0001) with greatest risk associated with G/G homozygosity (OR = 3.4, P < 0.0001). IL-1RN VNTR 1/1 homozygotes also occurred more frequently in RAS (OR = 2.0, P < 0.02). Inheritance of the G/G genotype of both IL-1B and IL-6 was a particularly strong predictor for RAS (OR = 8.5).     

Renin-angiotensin system gene polymorphisms predict the progression to renal insufficiency among Asians with lupus nephritis

The renin-angiotensin system (RAS) is a strong candidate as a mediator for the development and progression of lupus nephritis (LN). We performed an ethnically stratified analysis of 642 systemic lupus erythematosus (SLE) patients to determine whether various functional RAS gene polymorphisms are associated with SLE renal outcomes. Patients were genotyped for two angiotensin-converting enzyme (ACE) gene polymorphisms: Alu insertion/deletion (I/D) and 23 949 (CT)(2/3), and for two angiotensinogen (Atg) gene polymorphisms: M235T and C-532T. Multivariate analyses demonstrated associations between the ACE I/D, ACE (CT)(2/3) and Atg C-532T functional polymorphisms and LN among Asians. In stratified analyses among LN cases according to high vs low glomerular filtration rate (GFR), associations remained significant for the ACE D (odds ratio (OR) 5.9, P=0.001) and (CT)(2) (OR 6.2, P=0.001) alleles among Asian subjects with low GFR. Lastly, we found allelic dose-dependent associations between the ACE I/D (P=0.003), ACE (CT)(2/3) (P=0.005) and Atg M235T (P=0.04) polymorphisms, and GFR analyzed as a continuous variable among Asians. These findings suggest a significant role for ACE and Atg gene sequence variation and severity of LN among Asians with SLE.     

Association analysis between the interaction of RAS family genes mutations and papillary thyroid carcinoma in the Han Chinese population

Papillary thyroid carcinoma (PTC) is the major subtype of thyroid cancer, accounting for 75%-85% of all thyroid malignancies. This study aimed to identify the association between the interactions of single nucleotide polymorphisms (SNPs) in RAS family genes and PTC in the Han Chinese population, to provide clues to the pathogenesis and potential therapeutic targets for PTC. Hap Map and NCBI-db SNP databases were used to retrieve SNPs. Haploview 4.2 software was used to filter SNPs based on specific parameters, six SNPs of RAS gene (KRAS-rs12427141, KRAS-rs712, KRAS-rs7315339, HRAS-rs12628, NRAS-rs14804 and NRAS-rs2273267) were genotyped by matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF-MS) in 673 PTC patients and 657 healthy controls, the interactive effect was evaluated by crossover analysis, logistic regression and GMDR software.We found that genetic mutation in rs712 have significant associations with PTC risk after Bonferroni correction (p<0.001). The interaction between KRAS-rs12427141 and HRAS-rs12628 increased the risk of PTC (U=-2.119, p<0.05), the interaction between KRAS-rs2273267 and HRAS-rs7315339 reduced the risk of PTC (U=2.195, p<0.05). GMDR analysis showed that the two-factor model (KRAS-rs712, NRAS-rs2273267) was the best (p=0.0107). Summarily, there are PTC-related interactions between RAS family genes polymorphisms in the Han Chinese population.     

Association study of interleukin‐1 family and interleukin‐6 gene single nucleotide polymorphisms in recurrent aphthous stomatitis

Recurrent aphthous stomatitis (RAS) is a common painful, ulcerative oral inflammatory disorder with unknown aetiology. Immune system and aberrant cytokine cascade deemed to be critical in outbreaks of RAS ulcers. Interleukin‐1 (IL‐1) and IL‐6 are the most potent pro‐inflammatory cytokines. Single nucleotide polymorphisms (SNPs) of IL‐1 and IL‐6 genes can affect the secretion of these cytokines. The aim of this study was to investigate the association between RAS and IL‐6 and IL‐1 in Iranian subjects with minor RAS. Genomic DNA was obtained from 64 Iranian patients with RAS. IL‐1α C ?889 T, IL‐1β C ?511 T, IL‐1β C +3962 T, IL‐1R C pst‐I 1970 T, IL‐1Ra C Mspa‐I11100 T, IL‐6 C ?174 G and IL‐6 A nt +565 G polymorphisms were determined using polymerase chain reaction with sequence‐specific primers (PCR‐SSP). The frequency of C ?174 C genotype in the patients group was significantly different from the healthy control. No other significant differences were found in genotype and alleles frequencies between the two groups. These results indicate that certain SNPs of IL‐6 gene at position ?174 which located in promoter have association with predisposition of individuals to RAS.     

Interleukin-10 Gene Polymorphisms in Recurrent Aphthous Stomatitis

Recurrent aphthous stomatitis (RAS) is a common oral inflammatory disease with unknown etiology in which the immune system seems to have a role in oral tolerance. Interleukin (IL)-10 is a cytokine synthesis inhibitory factor. Single nucleotide polymorphisms (SNPs) of IL10 gene could alter this cytokine production. The aim of this study was to investigate frequencies of IL10 alleles and genotypes in a group of individuals with RAS. Genomic DNA of 60 Iranian patients with RAS were typed for IL10 gene (C/A ?1082, C/T ?819, and C/A ?592), using PCR-SSP method. Frequency of each allele and genotype was compared to control group.

A significantly higher frequencies of the T allele at position ?819 (p?=?0.006) and the A allele at position of ?592 (p?<?0.001) were found in the patients with RAS group, when compared to the controls. IL10 GA genotype at position ?1082 (p?=?0.007), CA genotype at position ?592 (p?=?0.001), and CT genotype at position ?819 (p?=?0.001) were significantly higher in the RAS patients. The results of this study suggest that certain SNPs of IL10 gene have association with predisposition of individuals to RAS. However, further multicenter studies should be conducted to confirm the results of this study.     

Interleukin-4 and Interleukin-4 Receptor Alpha Gene Polymorphisms in Recurrent Aphthous Stomatitis

ABSTRACT

Background: Recurrent aphthous stomatitis (RAS) is a common oral condition with a major impact on the quality of life. The condition is thought to be due to the overexpression of T helper-1(Th1)-related cytokines. Since interleukin-4 (IL-4) and its receptor (IL-4Rα) are antagonistic to Th-1 pathways, polymorphisms in their genes may also be involved in the pathogenesis of aphthous stomatitis.

Methods: Sixty-four patients diagnosed with minor RAS and 141 (age- and sex-matched) healthy controls were assessed for 3 single-nucleotide polymorphisms (SNPs) within the promoter region of the IL-4 gene (?1098G/T, ?590C/T, and ?33C/T), and 1 SNP in IL-4Rα gene (+1902 A/G).

Results: No significant differences were detected between the patient and the control group regarding IL-4 allele frequencies. However, the patient group demonstrated a higher frequency of IL-4 ?590 CC genotype and a lower rate of IL-4 ?590 TC genotype.

The TCT, GTT, GCT, and GTC haplotypes of the IL-4 gene (?1098, ?590, ?33) were significantly more frequent in the patients and the GCC, and TTT haplotypes were more common in healthy controls. No significant differences were found in IL-4Rα gene polymorphism between the 2 groups.

Conclusions: Certain polymorphisms of IL4 gene could predispose individuals to RAS.     

Angiotensin-converting enzyme 2 gene targeting studies in mice: mixed messages

As a major regulator of blood pressure homeostasis, the renin-angiotensin system (RAS) has been the subject of extensive scientific investigation. While the RAS was first discovered more than 100 years ago, several novel components of the system have been identified only in the last decade. One of these newer members of the RAS family is angiotensin-converting enzyme 2 (ACE2). Among the approaches used to establish a physiological role for ACE2 has been the generation of ACE2-null mouse lines using homologous recombination in embryonic stem cells. In the literature, there have been at least three lines of ACE2 knockout mice generated by gene targeting by different investigative groups. Interestingly, there are significant differences in some of the reported phenotypes of these distinct lines, especially with regard to their cardiovascular physiology. In this paper, we will review the results of published experiments using these ACE2-null mouse lines, highlighting similarities and differences in these studies and summarizing their contributions to our understanding of the physiological functions of this novel member of the RAS.