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.     

血管紧张素原基因T174M和M235T多态性与冠心病的相关性

目的研究血管紧张素原(AGT)基因T174M和M235T多态性与高血压并发冠心病的相关性.方法运用单管双相等位基因专一性扩增(single-tube bi-directional allele specific amplification,SB-ASA)方法,在中国人群中,对115例冠心病合并高血压病人、97例高血压对照者和90例正常对照者进行T174M和M235T基因分型.结果M235T多态C/C、C/T和T/T基因型在冠心病合并高血压组中的分布与正常对照和高血压对照相比差异均有显著性(P＜0.01);C、T等位基因频率与对照组相比差异也有显著性(分别为P＜0.05,P＜0.01).但在冠心病合并高血压组中,M235T的分布差异与冠状动脉粥样硬化病变程度无相关性.结论AGT基因M235T多态性可能是中国高血压病人并发冠心病的一个遗传性危险因素.     

血管紧张素原基因M235T多态性与老年脑梗死的相关性研究

目的 探讨血管紧张素原（angiotensinogen AGT）基因M235T分子变异与中国人脑梗死（cerebralinfarction CI）之间的关系。方法 采用聚合酶链反应（PCR）及限制性片段长度多态性分析（RFLP）法对75例CI、48例健康对照进行了AGT基因M235T多态性检测。结果 CI组AGT基因T235等位基因频率为0．78，235TT基因型频率为0．64，与对照组（分别为0．604和0．375）比较差异具有显著性（x^2=8.82P=0．003；x^2=8、27 P=0．004）。校正了CI的几种危险因素（血总胆固醇、血糖及年龄）后，235TT基因型仍可使CI发生的危险性增加（分别为OR=3．289，P=0．036；OR=2．49，P=0．023）。结论 AGT基因235TT型可能是中国人群CI发病的独立危险因素。     

Single Strand Conformation Polymorphism (SSCP) as a quick and reliable method to genotype M235T polymorphism of angiotensinogen gene

OBJECTIVES: Conflicting results on the relationship between M235T polymorphism of angiotensinogen (AGT) gene and diabetic nephropathy are reported in the literature, probably due to the small number of subjects, to different inclusion criteria and the different genotype analysis methods used. The aim of the present study was to set up a fast, cheap and reliable method to allow the genotyping of M235T polymorphism in a large number of subjects. DESIGN AND METHODS: We developed in our laboratory a new specifically designed PCR-SSCP method for M235T genotyping whose specificity was compared with that of Allele Specific PCR (ASPCR) and Mutagenically Separated PCR (MS-PCR). The exact M235T genotype was estabilished by direct sequencing. The new PCR-SSCP method was then used to genotype a population of 1171 hypertensive, normoalbuminuric type II diabetes mellitus patients. The patients were also genotyped for ACE I/D polymorphism. For comparison a group of hypertensive non diabetic patients (n = 88) were also screened. RESULTS: The PCR-SSCP method identified the M235T polymorphism with no misinterpretation at variance with ASPCR and MS-PCR methods that showed a preferential amplification of the T allele. The rare Y248C polymorphism of the AGT gene was also detected by PCR-SSCP. In diabetic hypertensive patients the prevalence of TT genotype was higher than in normotensive healthy controls and equivalent to that found in hypertensive non diabetic patients. CONCLUSIONS: The PCR-SSCP method for detection of M235T polymorphism is a powerful and sensitive tool for rapid, cheap and efficient screening of a large number of samples. The results obtained with this method demonstrate an association of the TT genotype of AGT gene with hypertension, both in diabetic and non diabetic patients.     

IgA肾病患者AGT M235T基因多态性分析

目的探讨血管紧张素原(AGT)M235T基因多态性与上海地区IgA肾病(IgAN)遗传易感性及临床病理表现的相关性。方法选取上海地区经肾穿刺病理活检证实为IgAN患者105例和健康对照者120例,采用聚合链式反应-限制性片段长度多态性技术(PCR-RFLP)检测AGT M235T基因多态性,并比较不同基因型患者临床病理表现之间的相关性。结果 105例IgAN肾病患者的AGT M235T基因多态性与正常对照相比,基因型分布频率差异无统计学意义;年龄、性别、血压、血清肌酐、24 h尿蛋白定量、初始的估算肾小球滤过率(eGFR)值等临床指标与AGT M235T基因型无相关性;病理资料显示AGT M235T各基因型病理表现无相关性。结论 AGT M235T基因多态性与IgAN患者无显著相关性。     

IgA肾病患者AGTM235T基因多态性分析

目的探讨血管紧张素原（AGT）M235T基因多态性与上海地区IgA肾病（IgAN）遗传易感性及临床病理表现的相关性。方法选取上海地区经肾穿刺病理活检证实为IgAN患者105例和健康对照者120例,采用聚合链式反应一限制性片段长度多态性技术（PCR—RFLP）检测AGTM35T基因多态性,并比较不同基因型患者临床病理表现之间的相关性。结果105例IgAN肾病患者的AGTM235T基因多态性与正常对照相比,基因型分布频率差异无统计学意义;年龄、性别、血压、血清肌酐、24h尿蛋白定量、初始的估算肾小球滤过率（eGFR）值等临床指标与AGTM235T基因型无相关性;病理资料显示AGTM235T各基因型病理表现无相关性。结论AGTM235T基因多态性与IgAN患者无显著相关性。     

醛固酮合成酶基因-344T/C多态性与缬沙坦降压疗效相关性分析

目的研究醛固酮合成酶基因-344T/C多态性与原发性高血压患者应用血管紧张素Ⅱ1型受体拮抗剂缬沙坦降压疗效的关系,以结合基因分型指导临床合理用药.方法多聚酶链反应-限制性片段长度多态性技术检测原发性高血压患者醛固酮合成酶基因-344T/C多态性;原发性高血压患者给予缬沙坦80 mg,1次/d,连续服用4周,比较不同基因型之间降压疗效.结果 TT基因型组收缩压和脉压下降幅度显著大于TC＋CC基因型组（P＜0.01）,而两组舒张压下降幅度差异无显著性（P＞0.05）.结论醛固酮合成酶基因-344T/C多态性与血管紧张素Ⅱ1型受体拮抗剂缬沙坦降压疗效存在相关性,无C等位基因原发性高血压患者对血管紧张素Ⅱ1型受体拮抗剂缬沙坦反应明显优于C等位基因携带者.     

原发性高血压左心室肥厚患者AGT(M235T)、ACE(I/D)基因协同效应探讨

目的　探讨血管紧张素原(AGT)(M235T)、血管紧张素转换酶(ACE)(I/D)对原发性高血压(EH)患 者发生左心室肥厚(EH LVH)的基因协同效应。方法　对中国四川籍汉族人群中109例EH患者,采用聚合酶 链反应(PCR)以及PCR限制性片段长度多态性(RFLP)方法检测ACE(I/D)、AGT(M235T)基因多态性;利用超 声心动图检测左心室质量(LVM)并计算左心室质量指数(LVEI)。结果　ACE(I/D)基因多态性D等位基因频 率在EH LVH组中明显增高(χ2=4.69,P=0.030),男性EH患者中,ACE(I/D)基因型构成比与LVH有关联(χ2 =9.55,P=0.008),协同存在AGT TT时,ACE(I/D)基因多态性与EH LVH有关(χ2=6.22,P=0.044),且D等 位基因在EH LVH明显增高(χ2=6.91,P=0.009),该类EH患者发生LVH的相对危险度增高(OR:2.50,95% CI:1.25～5.00)。结论　ACE(I/D)基因多态性D等位基因可能是LVH的独立危险因子,ACE基因多态性与 AGT基因多态性之间的协同效应表明,同时携带AGT TT型时,具有ACE(I/D)基因多态性D等位基因的EH患 者更易发生LVH。     

原发性高血压左心室肥厚患者AGT(M235T)、ACE(I/D)基因协同效应探讨

目的探讨血管紧张素原(AGT)(M235T)、血管紧张素转换酶(ACE)(I／D)对原发性高血压(EH)患者发生左心室肥厚(EH—LVH)的基因协同效应。方法对中国四川籍汉族人群中109例EH患者,采用聚合酶链反应(PCR)以及PCR限制性片段长度多态性(RFLP)方法检测ACE(I／D)、AGT(M235T)基因多态性;利用超声心动图检测左心室质量(LVM)并计算左心室质量指数(LVEI)。结果ACE(I／D)基因多态性D等位基因频率在EH—LVH组中明显增高(x^2=4．69,P=0．030),男性EH患者中,ACE(I／D)基因型构成比与LVH有关联(x^2=9．55,P=0．008),协同存在AGT-TY时,ACE(I／D)基因多态性与EH-LVH有关(x^2=6．22,P=0．044),且D等位基因在EH-LVH明显增高(x^2=6．91,P=0．009),该类EH患者发生LVH的相对危险度增高(OR：2．50,95％CI：1．25—5．00)。结论ACE(I／D)基因多态性D等位基因可能是LVH的独立危险因子,ACE基因多态性与AGT基因多态性之间的协同效应表明,同时携带AGT—TT型时,具有ACE(I／D)基因多态性D等位基因的EH患者更易发生LVH。     

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。     

Allelic polymorphism -491A/T in apo E gene modulates the lipid-lowering response in combined hyperlipidemia treatment

BACKGROUND: Combined hyperlipidemia (CHL) is one of the dyslipidemias more frequently found in clinical practice, and lipid-lowering drugs are often necessary in its management. Some genetic loci have been associated with CHL expression, and some studies have shown modulation of drugs efficiency in the treatment of dyslipidemias by genetic polymorphisms. We have investigated whether common polymorphisms and mutations in the apolipoprotein (apo) E, lipoprotein lipase (LPL), and apo CIII genes influence atorvastatin or bezafibrate responses in patients with CHL. DESIGN: One hundred and sixteen subjects participating in the ATOMIX study (Atorvastatin in Mixed dyslipidemia) were randomized to treatment with either atorvastatin or bezafibrate. Apolipoprotein E genotype and common -491A/T and -219T/G polymorphisms in the apo E gene promoter region, Sst I polymorphism in the apo CIII gene (3238C/G), and D9N and N291S common mutations in the LPL gene were determined by polymerase chain reaction (PCR) and restriction enzyme digestion. RESULTS: Statistical analysis showed the influence of the -491A/T polymorphism in atorvastatin and bezafibrate treatments. Subjects carrying the -491T allele showed an increased LDL-cholesterol-lowering effect with atorvastatin compared with -491T allele noncarriers (-35% vs. -27%, P = 0.037). Subjects carrying the -491T allele, when on bezafibrate treatment, showed a lower triglyceride reduction compared with -491T allele noncarriers (-23% vs. -39%, P = 0.05). CONCLUSIONS: In our study, the -491A/T polymorphism in the apo E gene promoter region modulated the lipid-lowering efficiency of atorvastatin and bezafibrate in CHL patients. Such influence might explain some of the interindividual response variabilities observed for the two drugs, and could help in CHL management.     

Angiotensinogen gene and hypertension in Chinese.

The renin-angiotensin system plays a major role in regulating blood pressure and maintaining electrolyte and volume homeostasis. Previously, the angiotensinogen gene, which encodes the key substrate for renin within this system, has been reported linked to and associated with essential hypertension in White Europeans, African-Caribbeans, and Japanese. Therefore, we investigated whether the angiotensinogen gene might be similarly implicated in the pathogenesis of essential hypertension in Chinese by carrying out linkage analysis in 310 hypertensive sibling pairs. Genotypes for two diallelic DNA polymorphisms observed at amino acid residues 174 (T174M) and 235 (M235T) within the coding sequence and for two highly informative dinucleotide (GT)-repeat sequences (one in the 3' flanking region, and one at a distance of 6.1 cM from the gene) were determined. Affected sibpair analysis conducted according to three different algorithms (S.A.G.E./SIBPAL, MAPMAKER/ SIBS, and APM methods) revealed no evidence for linkage of the angiotensinogen gene to hypertension. Our data indicate that molecular variants of this gene do not appear to contribute materially to the pathogenesis of primary hypertension among Chinese (a notion supported by concomitant, direct estimates of power), and that the disease relevance of this gene may vary therefore depending on ethnicity.     

Intercellular Adhesion Molecule-1 K469E and Angiotensinogen T207M Polymorphisms in Coronary Slow Flow

Objective

To investigate intercellular adhesion molecule-1 (ICAM1) and angiotensinogen (AGT) gene polymorphisms, as related to atherosclerosis and endothelial dysfunction, in coronary slow flow (CSF).

Subjects and Methods

The participants in this study were 48 patients with CSF and 67 patients with normal coronary flow as controls. The K469E polymorphism of ICAM1 (rs5498) and the T207M polymorphism of AGT (rs4762) were determined using the polymerase chain reaction amplification method.

Results

Baseline demographic parameters were similar in both groups. The mean thrombolysis in myocardial infarction frame count was significantly higher in patients with CSF (23.8 ± 5.1) compared to the controls (13.3 ± 2.6, p < 0.001). A significant association was found between the ICAM1 K allele and CSF (OR: 1.96, 95% CI: 1.15–3.35, p = 0.013). There was no difference in the frequency of AGT T207M genotypes in the patients with CSF and the control subjects.

Conclusion

This study showed that K469E polymorphisms of ICAM1 that play a role in atherosclerotic pathogenesis are related to CSF.Key Words: ICAM1 polymorphism, Angiotensinogen polymorphism, Coronary slow flow, Atherosclerosis     

谷胱甘肽S转移酶基因多态性与乳腺癌化疗疗效的关系

目的 观察乳腺癌患者谷胱甘肽S转移酶（GSTs）基因多态性与化疗敏感性之间的关系。 方法 收集接受蒽环类为基础化疗且具有完整疗效评价资料的132例原发性乳腺癌患者化疗前静脉血,检测GSTP1（A314G）、GSTA1（C69T）、GSTM1（缺失）和GSTT1（缺失）基因型,开展基因多态性与乳腺癌化疗疗效关系的分析。结果 在132例含蒽环类方案的化疗患者中,GSTP1基因型AA的有效率（56.3%）明显低于AG和GG（75.0%和100.0%;χ^{2=6.842,P<0.01）,且A等位基因与GSTT1（未缺失）及GSTT1（未缺失）+GSTM1（未缺失）+GSTA1携带野生型的组合,有效率为54.5%或46.9%,也明显低于其相应各组（72.6%,χ2=4.475,P<0.05及69.2%,χ2=5.100,P<0.05）。其中90例患者同时接受紫杉醇治疗,其GSTM1未缺失者的有效率（50.0%）低于缺失者的有效率（76.5%,χ2=6.722,P=0.01）,且未缺失者与GSTT1（未缺失）+GSTP1携带野生型+GSTA1携带野生型组合的有效率为41.7%,也明显低于其他患者（74.6%,χ2=8.128,P<0.01）。 结论 乳腺癌患者GSTs基因多态性检测可能有助于乳腺癌蒽环类和/或紫杉醇类药物疗效的预测。}     

MTHFR C677 T gene polymorphism in lymphoproliferative diseases

Methylenetetrahydrofolate reductase (MTHFR), a key enzyme in folate metabolism, has been implicated in cancer risk. In the present study we used a melting curve analysis to investigate the association of the common MTHFR C677 T polymorphism with lymphoproliferative diseases. Patients (n=117) were compared with age- and sex-matched control subjects (n=154). Our results indicate that the 677 T variant occurred less frequently in patients (26%) than in the control group (33.7%; P=0.05). Investigation of the variant allele (677 T) frequency in the subgroups with Hodgkin's lymphoma (HL) and B-cell neoplasms (BCNs) revealed that this difference was a result of the significantly lower distribution of the variant allele in patients with HL (20.5%; P=0.01). This was accompanied by a significantly higher frequency of the homozygote normal genotype (677CC) among the patients with HL. In patients with BCNs the distribution of the variant allele (30.3%) was comparable to that in the control group (P=0.47). However, the difference between HL (20.5%) and BCNs (30.3%) did not reach statistical significance (P=0.09). Our results suggest that the distribution of the C677 T polymorphism may vary among lymphoproliferative diseases.     

应用糖皮质激素患者护骨素基因T950C多态性与骨量的关系

目的:分析应用糖皮质激素患者护骨素基因启动子T950C单核苷酸多态性与骨密度及骨生化指标的相关性。方法:选择2004-03/2005-06在哈尔滨医科大学附属第二医院肾内科就诊的应用糖皮质激素六七个月的慢性肾小球肾炎患者138例,另外选择126例门诊健康体检者作为正常对照组,调查和取样均征得两组受试者本人同意。应用聚合酶链反应-限制性片断长度多态性方法测定两组观察对象护骨素基因启动子T950C的基因型;应用双能X射线骨密度仪测定两组观察对象股骨、腰椎等部位的骨密度;同时检测骨代谢生化指标,测定血清骨钙素应用放射免疫法,测定甲状旁腺激素应用化学发光法。结果:进入结果分析应用激素组138例,正常对照组126例。①两组观察对象护骨素基因型的分布:启动子T950C发现TT、TC、CC3种基因型,各基因型分布频率正常对照组为TT26.98%,TC48.41%,CC24.61%,应用激素组为TT27.54%,TC48.55%,CC23.91%,两组间比较差异无显著性意义(P>0.05)。②T950C不同基因型观察对象骨密度、生化指标的比较:正常对照组3种基因型之间骨密度比较,差异无显著性意义(P>0.05);应用激素组各部位骨密度呈现CC>TC>TT的趋势,但差异无显著性意义(P>0.05)。两组各基因型之间骨代谢生化指标的差异均无显著性意义(P>0.05)。结论:应用糖皮质激素患者的护骨素基因T950C基因型与正常人群比较无明显差异,提示护骨素基因T950C基因型与肾小球肾炎的发病无关;护骨素基因T950C多态性与各部位骨密度无明显相关,推测可能与应用糖皮质激素后的骨量丢失无关。     

应用糖皮质激素患者护骨素基因T950C多态性与骨量的关系

目的：分析应用糖皮质激素患者护骨素基因启动子T950C单核苷酸多态性与骨密度及骨生化指标的相关性。 方法：选择2004-03／2005—06在哈尔滨医科大学附属第二医院肾内科就诊的应用糖皮质激素六七个月的慢性肾小球肾炎患者138例，另外选择126例门诊健康体检者作为正常对照组，调查和取样均征得两组受试者本人同意。应用聚合酶链反应-限制性片断长度多态性方法测定两组观察对象护骨素基因启动子T950C的基因型；应用双能X射线骨密度仪测定两组观察对象股骨、疆椎等部位的骨密度；同时检测骨代谢生化指标，测定血清骨钙素应用放射免疫法，测定甲状旁腺激素应用化学发光法。 结果：进入结果分析应用激素组138例，正常对照组126例。①两组观察对象护骨素基因型的分布：启动子T950C发现TT、TC、CC3种基因型，各基因型分布频率正常对照组为TT26．98％，TC48．41％，CC24．61％，应用激素组为TT27．54％，TC48．55％，CC23．91％，两组间比较差异无显著性意义（P〉0．05）。②T950C不同基因型观察对象骨密度．生化指标的比较：正常对照组3种基因型之间骨密度比较。差异无显著性意义（P〉0．05）；应用激素组各部位骨密度呈现CC〉TC〉TT的趋势，但差异无显著性意义（P〉0．05）。两组各基因型之间骨代谢生化指标的差异均无显著性意义（P〉0．05）。 结论：应用糖皮质激素患者的护骨素基因T950C基因型与正常人群比较无明显差异，提示护骨素基因T950C基因型与肾小球肾炎的发病无关；护骨素基因T950C多态性与各部位骨密度无明显相关，推测可能与应用糖皮质激素后的骨量丢失无关。     

Angiotensin I-converting enzyme gene polymorphism and drug response.

An insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene has been described in chromosome 17q23 of the human genome. Subjects with the genotype DD have markedly higher plasma ACE levels than those with genotype II; although ACE concentration in plasma is not rate-limiting for the production of angiotensin II, it has been suggested that the renin-angiotensin system may have an enhanced role in cardiovascular homeostasis in subjects with DD genotype or D allele. Meta-analysis confirmed the association of the D allele with an increased risk of myocardial infarction and stroke, but these relations are still uncertain with longevity and renal deterioration. Otherwise, I allele seems to be related with an improved response to physical training. The I/D polymorphism of the ACE gene is not a marker for any form of hypertension, though some conflicting results have been described. Nevertheless this polymorphism may have an influence on the antihypertensive response, particularly when using ACE inhibitors (ACEI). For example, blood pressure normalization with captopril in patients suffering from cardiac failure would be more effective in II genotype; conversely, both regression in left ventricular hypertrophy and improvement in diastolic filling would be greater after long-term treatment with enalapril in patients with essential hypertension and DD genotype. Conflicting results were also described using ACEI as a renoprotective therapy. This review therefore supports the justification for further evaluation in appropriately powered studies.