Angiotensinogen gene M235T variant and pre-eclampsia in Romanian pregnant women

Background. Association between the human angiotensinogen gene and essential hypertension has been confirmed in recent studies. Pre-eclampsia is a complication of pregnancy characterised by increased vascular resistance, high blood pressure, proteinuria and oedema, that appears in the second and third trimester of pregnancy. The aim of our study was the analysis of M235T mutation in the gene encoding angiotensinogen in Romanian women with different forms of hypertension during pregnancy. Methods. Fourteen women with obstetric complications were tested for M235T angiotensinogen gene mutation. Indications for testing were: severe or mild pre-eclampsia and pre-eclampsia associated with chronic hypertension. We also tested for control 6 healthy women. The M235T angiotensinogen gene mutation was analysed by polymerase chain reaction followed by enzymatic digestion with Tth 111I restriction endonuclease enzyme and agarose gel electrophoresis of the products. Results. Eleven (78.57%) of the 14 women with complications of pregnancy had M235T mutation: 9 (64.28%) were found to be heterozygous carriers of the M235T variant of the angiotensinogen gene and 2(14.28%) were found to be homozygous carriers. In the group of women with normal pregnancy, 3 (50%) of the 6 women had M235T mutation: 2 (33.33%) were found to be heterozygous carriers of the M235T variant of the angiotensinogen gene and 1 (16.66%) was found to be homozygous carrier. Conclusions. Our study shows that the M235T variant in the gene encoding angiotensinogen could be a risk factor in mild and severe pre-eclampsia.     

Association of T174M polymorphism of angiotensinogen gene with essential hypertension: A meta-analysis

The association between T174M polymorphism of angiotensinogen gene and essential hypertension risk remains controversial. We herein performed a meta-analysis to achieve a reliable estimation of their relationship. All the studies published up to May 2013 on the association between T174M polymorphism and essential hypertension risk were identified by searching the electronic repositories PubMed, MEDLINE and EMBASE, Springer, Elsevier Science Direct, Cochrane Library and Google Scholar. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) were calculated. Ultimately, nine eligible studies, including 2188 essential hypertension cases and 2459 controls, were enrolled in this meta-analysis. No significant associations were found under the overall ORs for M-allele comparison (M vs. T, pooled OR 0.92, 95% CI 0.62–1.37), MM vs. TT (pooled OR 0.86, 95% CI 0.29–2.51), TM vs. TT n (pooled OR 0.91, 95% CI 0.63–1.32), recessive model (MM vs. TT+TM, pooled OR 0.89, 95% CI 0.35–2.30), dominant model (MM+TM vs. TT, pooled OR 0.91, 95% CI 0.60–1.38) between T174M polymorphism and risk for essential hypertension. This meta-analysis suggested that the T174M polymorphism of the angiotensinogen gene might not be associated with the susceptibility of essential hypertension in Asian or European populations.     

Association of the T174M Polymorphism of the Angiotensinogen Gene with Essential Hypertension in Russians and Tatars from Bashkortostan

The alleles and genotypes of the T174M polymorphism of the angiotensinogen gene were PCR-analyzed in Russians and Tatars from Bashkortostan. The genotype frequency distribution observed in either ethnic group did not differ from that reported for other populations. The T174M polymorphism was tested for association with essential hypertension (EH). Genotypes TT, TM, and MM were found respectively in 82.56, 13.95, and 3.49% normotensive Russians and in 83.81, 16.19, and 0% normotensive Tatars. The frequency of genotype TM in patients with EH onset beyond 45 years of age was significantly higher than in controls of the same age without signs of cardiovascular disorders (51.72 vs. 11.11% in Russians and 45.45 vs. 16% in Tatars). Patients with EH onset under 45 did not differ in genotype frequency distribution from normotensive subjects of the same age. Genotype TM was associated with higher risk of EH in people over 45.     

高血压患者血管紧张素原基因调控及与细胞因子关系的研究

在高血压患者中研究血管紧张素原(AGT)基因M235T多态性、等位基因分离及与细胞因子的关系。采用聚合酶链反应结合内切酶消化进行AGT基因型分析。用双抗体夹心ELISA酶联法测定细胞因子(IL-1、IL-6、TNF)。分析高血压病组和对照组的血管紧张素原(AGT)基因235位氨基酸残基的基因型及等位基因频率,并分析细胞因子对AGT基因M235T变异的影响。结果表明：高血压组中AGT 235为TT型38例(55．88％),TM型24例(35．29％),MM型6例(8．82％),其T型和M型等位基因频率分别为73．53％和26．47％。对照组中开型28例(47．46％),TM型25例(42．37％),MM型6例(10．17％),T型和MM型等位基因频率分别为68．65％和31．35％。在AGT 235T等位基因型组中,高血压病组IL-1、IL-6、TNF浓度显著高于对照组。在AGT 235M等位基因型组中,TNF浓度高于对照组。无论大于60岁或小于60岁的高血压病与相应年龄对照组比较,IL-1、IL-6、TNF浓度均显著升高。而在高血压病或对照组内,大于60岁组与小于60岁组之间比较,IL-1、IL-6、TNF浓度均无显著性差异。说明IL-1、IL-6、TNF升高与疾病有关而与年龄无关。研究结论：高血压病AGT 235TT型和T等位基因频率高于健康对照。AGT 235TT型和T等位基因频率增高可能与高血压发生和发展有关。在AGT 235T型等位基因频率增高的人群中,细胞因子IL-1、IL-6、TNF增高可能促进高血压发病。细胞因子对高血压病患者AGT 235TT型转录及表达可能有一定的调控作用。     

慢性动脉血压调节与原发性高血压病——Ⅱ.原发性高血压病

原发性高血压病的发生原因和发病机理十分复杂,很多问题目前并不十分清楚。通过近几十年的研究,大家比较一致的看法是,原发性高血压病的内因是肾脏功能的损伤,其发生条件（外因）是摄取的食盐（钠）过多。人类饮食中添加食盐已有几千年的历史,它是人类文明发展的一种表现。然而各种研究的结果表明,食盐的过量摄取的确是高血压的元凶。此外,原发性高血压多见于老年人。由于有这些特点,因此原发性高血压病常常被看成是一种“文明”病,一种肾脏的疾病,一种老年人常见的病。本文将对这些特点作进一步的分析和讨论。     

Association of angiotensinogen M235T gene polymorphism with end-stage renal disease risk: a meta-analysis

Association between angiotensinogen (AGT) M235T gene polymorphism and end-stage renal disease (ESRD) risk is still controversial. This meta-analysis was performed to evaluate the association of AGT M235T gene polymorphism with ESRD susceptibility. A predefined literature search and selection of eligible relevant studies were performed to collect data from electronic databases of PubMed, Embase and Cochrane Library. Sixteen literatures were identified for the analysis of association of AGT M235T gene polymorphism with ESRD risk. T allele and TT genotype were associated with ESRD susceptibility in Caucasians (T: OR = 1.13, 95 % CI: 1.02–1.25, P = 0.02; TT: OR = 1.22, 95 % CI: 1.03–1.45, P = 0.02). However, MM genotype might not play a protective role against ESRD risk in Caucasians. Furthermore, there was no a markedly positive association between AGT M235T gene polymorphism and ESRD susceptibility in overall populations, Asians and Africans. In conclusion, T allele or TT homozygote is associated with the onset of ESRD in Caucasians. However, more studies should be performed in the future.     

重庆居民5-HT2A基因多态性与原发性高血压关系

以聚合酶链PCR法分析重庆市一般人群的5-HT2A基因C102T多态性(样本总数348人,其中高血压组:HT=137例,非高血压组:NT=211例)的临床指标间的相关性与频率分布。了解重庆地区汉族人群5-羟色胺受体2基因(5-hydroxytryptamine receptor gene,5-HT2A)C102T多态性与原发性高血压病(essential hypertension,EH)的关系。卡方检验结果显示5-HT2A的C102T基因多态性(P=0.549)与等位基因频率(P=0.263)在HT与NT之间没有显著性统计学差异;5-HT2A的C102T基因多态性与高血压logistic回归模型分析结果显示也未见显著性差异,卡方值(Wald)为0.399;比值比为0.884;95%的可信区间为0.603~1.296,P值为0.528。一般线性模型分析结果:5-HT2A基因C102T多态性与收缩压,舒张压之间没有显著性统计学差异,PSBP=0.868,PDBP=709。5-HT2A的C102T多态性可能与重庆汉族人群EH无关。     

The angiotensinogen gene M235T polymorphism and acute myocardial infarction risk: a meta-analysis of 22 studies

Angiotensinogen, one of the most important proteins in the renin–angiotensin system, plays a key role in the progress of coronary heart disease and myocardial infarction (MI). Many studies have investigated the association between angiotensinogen gene M235T polymorphism and MI risk, but the results were inconsistent. We performed a meta-analysis of 22 studies on M235T polymorphism and MI risk published before November 2012. This meta-analysis included a total of 4,606 MI cases and 4,918 controls. Overall, the per-allele odds ratio (OR) of the 235T variant for total MI risk was 1.04 (95 % CI 0.92–1.17). When a recessive model was evaluated, the OR was 1.06 (95 % CI 0.96–1.17) and under a dominant model, the OR was 0.96 (95 % CI 0.82–1.11). Under pairwise comparisons, non-significant associations were found between M235T polymorphism and MI risk (MT vs. MM, OR, 0.96, 95 % CI 0.87–1.06; TT vs. MM, OR, 1.03, 95 % CI 0.83–1.28). Subgroup analyses in the different ethnic groups and different control sources were performed and no significant association was found also. Based on the available evidence, no association between M235T polymorphism and MI risk was observed, even in the sub-analysis concerning different races and control sources. The direction of further research should focus not only on the simple relationship of M235T polymorphism and MI risk, but also on gene–gene and gene-environment interaction.     

内蒙古地区达斡尔族血管紧张素转换酶基因多态性分布

目的:研究内蒙古地区达斡尔族血管紧张素转换酶基因(ACE)多态性分布。方法:采用聚合酶链反应检测198例北方汉族和198例达斡尔族中血管紧张素转换酶基因插入/缺失(I/D)多态性分布。结果:ACE基因多态性,达斡尔族人群ID、DD基因频率高于北方汉族,II基因频率低于北方汉族,二组间比较均存在明显差异(P<0.05)。结论:北方汉族与达斡尔族间ACE基因多态性和等位基因频率分布存在差异。     

AGT基因SNPs与哈萨克族高血压左室肥厚关系的研究

目的探讨血管紧张素原基因（angiotensinogen gene,AGT）-6A／G,-20A／C,M235T和T174M 4个单核苷酸多态性（single nucleotide polymorphisms,SNPs）与新疆哈萨克族高血压患者左室肥厚的关系。方法采用低渗溶血法破裂血细胞、蛋白酶K消化、饱和酚／氯仿抽提法提取白细胞基因组DNA。采用聚合酶链反应-限制性片断长度多态性（polymerase chain reaction—restriction fragment length polymorphism,PCR-RFLP）技术进行个体基因型分型。结果①在不考虑年龄、高血压病史时间、性别及收缩压、舒张压对左室肥厚的影响的前提下,未发现-6A／G、-20A／C与哈萨克族高血压左室肥厚的相关关系。②在以性别作为亚变量的分析结果中,我们发现-6A／G和-20A／C分别与哈萨克族女性和男性高血压左室肥厚相关。③不同SNPs间的配对连锁不平衡分析结果显示,除M235T与T174M之间外,其他各位点间存在有统计学意义的连锁不平衡关系。④单体型分析结果发现,研究人群AGT基因-6A／G、-20A／C、M235T和T174M4个SNPs构成了11种主要的单体型,其中H2（A—G—M—T）、H5（C—A—M—M）、H6（C—A-T—T）、H9（C-A—T—M）的频率在左室肥厚、非左室肥厚两组的分布存在差异,且具有统计学意义（P〈0．05）。结论AGT基因-6A／G、-20A／C、M235T和T174M变异可能与新疆哈萨克族高血压左室肥厚有关。     

Polymorphism of angiotensinogen gene M235T in myocardial infarction and brain infarction: a meta-analysis

The angiotensinogen (AGT) gene M235T polymorphism has been reported to be associated with myocardial infarction (MI) and brain infarction (BI), but the results remain inconclusive. This meta-analysis was designed to clarify these controversies. Electronic databases were systematically searched before February 2013. A total of 38 studies with 17304 subjects met our inclusion criteria. In East Asian group, significant association was found between AGT M235T polymorphism and risk of MI (for dominant model: OR = 1.79; 95% CI = 1.04–3.06; for recessive model OR = 2.01; 95% CI = 1.21–3.36; for additive model OR = 1.79; 95% CI = 1.14–2.86) as well as BI (for dominant model: OR = 1.66; 95% CI = 1.22–2.27; for recessive model OR = 1.78, 95% CI = 1.29–2.46; for additive model: OR = 1.64, 95% CI = 1.34–2.00), while the M235T polymorphism did not impact the risk of MI in total population and other ethnicity. In the subgroup analyses by gender and age, there was lack of evidence for the association. This meta-analysis suggested an association between the M235T polymorphism and MI as well as BI in East Asian population. Further studies with larger numbers of worldwide participants are needed to understand the genetic basis of MI and BI.     

Relations of blood pressure to angiotensinogen gene T174M polymorphism and alcohol intake

To clarify the interactive effects of alcohol intake and angiotensinogen gene codon 174 (T174M) polymorphisms on blood pressure in Japanese male workers. On the basis of data from health examinations, nutrition survey and T174M genotype analysis conducted for 185 Japanese male workers at 2000, the prevalence of high-normal blood pressure (HNBP) and hypertension were compared between the four subgroups crossed by two T174M genotype categories ('TT' type, and 'TM or MM' type) and two alcohol intake categories (less than 13.7 g per day, and 13.7 g or more per day). Furthermore, for 95 subjects who had been normotensive at 1998 among them, risk of development into HNBP or hypertension at 2000 were compared across the four subgroups. The findings showed that the HNBP prevalence adjusted for age, body mass index, smoking habits and sodium intake in 2000 was significantly (p=0.03) greater in 'TM or MM' type (57.9%) than in 'TT' type (24.9%) in subjects with 13.7 g or more of daily alcohol intake, whereas no difference in this parameter was found between the two genotypes in those with less than 13.7 g of daily alcohol intake (18.2% and 18.3%, respectively). The risk for development into HNBP at 2000 was also greatest in 'TM or MM' type with 13.7 g or more of daily alcohol intake among the four subgroups, although there were not significant differences between the four subgroups. The prevalence of hypertension or development risk for hypertension did not significantly differ between the four subgroups. Therefore, it can be seen that alcohol drinking might be specifically associated with the HNBP in M allele carriers of angiotensinogen gene T174M polymorphism.     

A 4-base-pair deletion polymorphism in man

Partial nucleotide sequencing of C11p11, a probe mapping close to the gene determining familial adenomatous polyposis (FAP) on human chromosome 5, in 4 unrelated persons has revealed a 4-base-pair deletion variant designated DELI at an arbitrary DNA locus D5S71. For screening the deletion variants that may frequently occur in the non-coding DNA sequences, we set up a non-invasive procedure which involves DNA amplification by PCR, simple polyacrylamide gel electrophoresis and direct visualisation of alleles under long wave ultraviolet light by ethidium bromide staining.     

Association of the T174M polymorphism of the angiotensinogen gene with essential hypertension in Russians and Tatars from Bashkortostan

The alleles and genotypes of the T174M polymorphism of the angiotensinogen gene were PCR-analyzed in Russians and Tatars from Bashkortostan. The genotype frequency distribution observed in either ethnic group did not differ from that reported for other populations. The T174M polymorphism was tested for association with essential hypertension (EH). Genotypes TT, TM, and MM were found respectively in 82.56, 13.95, and 3.49% normotensive Russians and in 83.81, 16.19, and 0% normotensive Tatars. The frequency of genotype TM in patients with EH onset beyond 45 years of age was significantly higher than in controls of the same age without signs of cardiovascular disorders (51.72 vs. 11.11% in Russians and 45.45 vs. 16% in Tatars). Patients with EH onset under 45 did not differ in genotype frequency distribution from normotensive subjects of the same age. Genotype TM was associated with higher risk of EH in people aged beyond 45.     

Variation at the M235T locus of the angiotensinogen gene and essential hypertension: a population-based case-control study from Rochester,Minnesota

A variant of the angiotensinogen gene, M235T, has been associated with essential hypertension in selected subjects from Paris, France and Salt Lake City, Utah. In the present report, we studied a population-based sample consisting of 104 subjects diagnosed with hypertension before age 60 and 195 matched normotensive individuals from Rochester, Minnesota. We determined whether there was a relationship between the M235T polymorphism of the angiotensinogen gene and the occurrence of essential hypertension using two methods. First, a contingency chi-square analysis was carried out to test for an association between the M235T polymorphism and hypertension status. Second, multivariable conditional logistic regression was used to determine whether variation at the M235T polymorphism was a significant predictor of the probability of having essential hypertension. We detected no statistically significant association between the M235T polymorphism and the occurrence of essential hypertension. In particular, the association was not significant in either gender or in a subset of severely hypertensive subjects requiring two or more anti-hypertensive medications. Furthermore, variation in the number of M235T alleles did not make a significant contribution to predicting the probability of having essential hypertension, either alone or in conjunction with other predictor variables. These results suggest that the contribution of variation in the angiotensinogen gene to the occurrence of essential hypertension is less than initially suspected, or may not be constant across populations.     

Association of cytotoxic T lymphocyte-associated antigen 4 gene single nucleotide polymorphism with type 1 diabetes mellitus in Madurai population of Southern India

Type 1 diabetes mellitus formerly called juvenile diabetes, is an organ specific T-cell mediated autoimmune disease characterized by the progressive loss of function of the insulin producing beta-cells of the islets of Langerhans. Cytotoxic T lymphocyte-associated antigen 4 gene (CTLA-4) has been proposed as a candidate gene for conferring susceptibility to autoimmunity. Association of CTLA-4 gene polymorphism is well established in autoimmune endocrinopathies across world population. The present study was conducted to investigate the association of CTLA-4 exon 1 49A/G polymorphism with TIDM in Madurai, a city in Southern India. Fifty three clinically proven T1DM patients and 53 control subjects with no history of autoimmune disease were recruited for the study. Genomic DNA was extracted from peripheral blood. CTLA-4 exon 1 49 A/G polymorphism was assessed using PCR-RFLP methods. Our findings revealed a significant association of CTLA-4 exon 1 49 A/G polymorphism with T1DM in Madurai population.     

Transfer and expression of the human multiple drug resistance gene as potential human gene therapy

The human multiple drug resistance (MDR) gene has been used as a model for human gene transfer which could lead to human gene therapy. MDR is a transmembrane protein which pumps a number of toxic substances out of cells including several drugs used in cancer chemotherapy. Normal bone marrow cells express low levels of MDR and are particularly sensitive to the toxic effects of these drugs. There are two general applications of MDR gene therapy: (1) to provide drug-resistance to the marrow of cancer patients receiving chemotherapy, and (2) as a selectable marker which when co-transferred with a non-selectable gene such as the human beta globin gene can be used to enrich the marrow for cells containing both genes. We demonstrate efficient transfer and expression of the human MDR gene in a retroviral vector into live mice and human marrow cells including CD34⁺ cells isolated from marrow and containing the bulk of human hematopoietic progenitors. MDR gene transduction corrects the sensitivity of CD34⁺ cells to taxol, an MDR drug substrate, and enriches the marrow for MDR-transduced cells. The MDR gene-containing retroviral supernatant used has been shown to be safe and free of replication-competent retrovirus. Because of the safety of the MDR retroviral supernatant, and efficient gene transfer into mouse and human marrow cells, a phase 1 clinical protocol for MDR gene transfer into cancer patients has been approved to evaluate MDR gene transfer and expression in human marrow.