Renin-angiotensin system gene polymorphisms: assessment of the risk of coronary heart disease

BACKGROUND: Renin-angiotensin system genes are candidate genes in cardiovascular system diseases. Angiotensinconverting enzyme (ACE), angiotensinogen (AGT) and angiotensin II type 1 receptor (AT1R) gene polymorphisms are considered risk factors in coronary heart disease (CHD). AIM: To evaluate the involvement of the ACE, AGT and AT1R genetic variants in predisposition to CHD as well as their association with other known risk factors. METHODS: The study included 400 male subjects (200 with CHD and 200 healthy individuals). Genotypes were determined by a polymerase chain reaction (PCR). For the AGT and AT1R genes a restriction analysis of the PCR product was performed. The allele frequency and genotype distribution were compared between groups. RESULTS: The allele and genotype frequencies of the ACE gene were similar in both groups, however, a significantly higher frequency of the DD genotype was observed in the presence of hyperlipidemia (39% vs 24% in non-hyperlipidemic subjects, p<0.01). The AGT gene polymorphism was associated with the development of CHD. The T allele was significantly more frequent in patients than in the control group (55% vs 44%, p<0.05). The heterozygous MT genotype was observed in 61% of patients compared to 40% in the controls (p<0.05). The A1166C polymorphism of the AT1R gene was also associated with CHD as well as with age at the onset of disease. The frequency of the C allele was 29% compared to 21% in the control group (p<0.01) and the frequency of the CC homozygote was almost three times higher in patients. CONCLUSIONS: There is an association between molecular variants of the angiotensinogen and angiotensin II type 1 receptor and increased risk of CHD. The DD genotype of the ACE gene polymorphism and the TT genotype of the AGT gene polymorphism were significantly more frequent in patients with hyperlipidemia. The TT genotype of the AGT gene M235T polymorphism was associated with an increased risk of CHD and myocardial infarction only in smokers.     

冠心病患者对氧磷酯酶1基因多态性分析

目的 :探讨冠心病 (CHD)患者对氧磷酯酶 1(Paraoxonase 1,PON1)基因多态性与血脂的关系及其病因学意义。方法 :使用Taqman特异性等位基因鉴别法检测 93例CHD患者和 138例健康对照者的基因组DNA ,测定该基因G 12 6C、L5 5M和Q192R三个多态性的基因型和由三个位点的等位基因组成的单体型。统计分析两组间这些基因型和单体型频率分布差异性 ,以及不同基因型与血脂水平的相关性。结果 :CHD患者中Q192R位点的QQ基因型携带者明显少于健康对照者 (7.5 %∶18.1% ,P <0 .0 5 ) ,各种单体型在两组间差异无显著性意义。各基因型之间血脂水平差异亦无显著性意义。结论 :PON1基因中只有Q192R多态性与CHD的发病相关     

肾素-血管紧张素系统基因多态性与冠心病合并慢性心力衰竭严重程度的关系

目的检测部分中国南方汉族人群冠心病合并慢性心力衰竭患者的ACE及AGT基因多态性分布情况,以探讨肾素-血管紧张素系统（1／AS）基因多态性对冠心病合并慢性心力衰竭严重程度的影响。方法应用聚合酶链反应及限制性片断长度多态性技术,对210例冠心病合并慢性心力衰竭患者的ACE基因插入／缺失（I/D）及AGT基因M235T多态性进行检测,采用彩色多普勒检测患者的左室舒张末内径（LVDD）及左室射血分数（LVEF）。结果不同ACE基因型患者其LVDD及LVEF均存在差异,LVDD（DD）〉LVDD（ID）〉LVDD（II）（P〈0．05）,LVEF（DD）〈IXEF（ID）〈LVEF（II）（P〈0．05）,不同AGT基因型亚组间LVDD及LVEF差别均无统计学意义（P〉0．05）。结论ACE基因I／D多态性与中国南方部分汉族人群冠心病合并慢性心力衰竭的严重程度相关,DD型ACE基因的冠心病患者发生心力衰竭后病情较其他基因型者更加严重。AGT基因M235T多态性似与冠心病合并慢性心力衰竭的严重程度无关。     

雌激素受体基因多态性与冠心病关系的研究

目的　观察雌激素受体 (ER)基因多态性在中国汉族人群中的分布及其与冠心病 (CHD)的关系。方法　应用聚合酶链反应 (PCR)和限制性片段长度多态性 (RFLP)方法检测 1 35例CHD患者和 1 1 8例正常对照者ER基因型 ,结合血脂水平、选择性冠状动脉造影 (SCA)结果探讨两者间的关系。结果　ER等位基因X、x和P、p频率在冠心病组和对照组分别为 0 1 70、0 830 ,0 1 69、0 831 ;0 2 56、0 744,0 339、0 661。基因型频率分布符合Hardy Weinberg平衡定律。XbaⅠ酶切多态性基因型频率、等位基因频率及结合XbaⅠ和PvuⅡ两个酶切多态性分析在组内、组间比较差异均无显著性 (P >0 0 5) ,且ER基因型间血脂水平、SCA结果在组内比较均无统计学意义 (P >0 0 5)。但是 ,PvuⅡ酶切多态性在正常对照组与CHD组以及心肌梗死组与心绞痛组比较有明显差异 (P <0 0 5)。结论　在CHD人群中存在着ERXbaⅠ和PvuⅡ基因多态性 ,其中XbaⅠ酶切多态性与CHD无相关性 (P >0 0 5) ,而ERPvuⅡ酶切多态性与冠心病有相关性 (P <0 0 5) ,PvuⅡ基因多态性可能是CHD发病的危险因素之一。     

The renin-angiotensin system genetic polymorphisms and rheumatic mitral valve disease

BACKGROUND AND AIM OF THE STUDY: Angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism, angiotensinogen (AGT) gene polymorphism and angiotensin II type 1 receptor (AT1R) polymorphism in relation to rheumatic mitral valve disease were examined in a case-control study to investigate possible relationships between these gene polymorphisms and rheumatic mitral valve disease in patients undergoing mitral valve replacement (MVR). METHODS: A total of 50 patients with rheumatic mitral valve disease and undergoing MVR was compared with 50 normal, and age- and sex-matched control subjects. ACE I/D, AGT gene M235T and AT1R-adenine/cytosine 1166 (A1166C) genotype polymorphisms were identified by polymerase chain reaction (PCR) -based restriction analysis. RESULTS: ACE I/D polymorphism differed significantly between the groups. The control group mostly represented the heterozygote ID allele (74%), while the MVR group showed frequencies of 60% for the homozygote DD and II alleles. MM homozygote frequency was significantly greater in controls, but TT homozygote frequency was significantly greater in the MVR group. AT1R-A1166C genotype polymorphism also differed significantly between groups; the MVR group had 73.7% of the AC heterozygote allele, while controls had 64.4% of the AA and 66.7% of the CC homozygote alleles. CONCLUSION: These results provided evidence of an association between ACE I/D polymorphism, M235T polymorphism and AT1R-A1166C genotype polymorphism and rheumatic mitral valve disease.     

MTHFR基因多态性与冠心病的关系

目的研究天津地区人群N^5,N^10-亚甲基四氢叶酸还原酶（MTHFR）基因C677T多态性与冠心病的关系。方法应用聚合酶链反应（PCR）技术和限制性酶切片段长度多态性（RFLP）分析技术检测50例冠心病患者（冠心病组）和50例正常人（对照组）的MTHFR基因C677T多态性,应用高效液相色谱法测定血浆同型半胱氨酸（Hcy）水平,采用125I标记放免法测定血清叶酸浓度。结果1.冠心病组与对照组MTHFR基因频率分布不同（P〈0.05）,对照组CC型、TC型、TT型基因频率分别为52.0%,28.0%,20.0%,冠心病组分别为26.0%,44.0%,30.0%。冠心病组T等位基因频率为52.0%,C等位基因频率为48.0%,与对照组比较有显著性差异（P〈0.05）。2.两组的TT基因型者血浆Hcy浓度均明显高于CC和TC基因型者（P〈0.05）,而后两者间无显著性差异（P〉0.05）。3.冠心病组Hcy浓度高于照组（P〈0.05）,两组叶酸水平无显著性差异（P〉0.05）,血浆Hcy浓度与叶酸水平呈显著负相关（r分别为-0.617和-0.588,P〈0.05）。结论MTHFR基因C677T点突变与冠心病发病密切相关,MTHFR基因纯合突变是引起高Hcy血症的一个重要的遗传因素。     

昆明汉族人群肾素-血管紧张素系统基因多态性与糖尿病肾病的相关性研究

(ACE)基因多态性与糖尿病肾病(DN)的关系. 方法 采用聚合酶链反应-限制性片段长度多态性(PCR-RFLP)方法检测T2DM不伴DN患者74例(T2DM组)、DN患者120例(DN组)及60名健康体检者(对照组)的ACE I/D及AGT M235T基因型. 结果 (1)DN组ACE-DD基因型频率和D等位基因频率(分别为53%、71%)均高于T2DM组(分别为22%、46.6%)及对照组(分别为29%、45.5%)(P均＜0.01).(2)AGT M235T基因型频率和等位基因频率三组差异无统计学意义(P＞0.05).(3)同时携带ACE-DD及AGT-TT基因型者发生DN的OR值为6.183. 结论 (1)ACE-DD基因型和D等位基因可能是昆明地区汉族人群DN的易感因素.(2)未发现AGT M235T多态性单一因素与DN的发生有关联.(3)ACE-DD基因型与AGT-TT基因型可能在DN发生中有协同作用.     

P-selectin gene polymorphisms and risk of coronary heart disease among Tunisians

P-selectin plays a key role in inflammation and atherosclerosis, and polymorphic variants of P-selectin were implicated in the pathogenesis of atherosclerotic and inflammatory changes, including coronary heart disease (CHD) in many ethnic groups. We investigated the contribution of P-selectin promoter (−2123C/G, −1969G/A) and exon (Ser290Asn, Asn562Asp, Thr715Pro) polymorphisms to CHD genetic susceptibility among 298 Tunisian CHD patients and 339 controls. Minor allele and genotype frequencies of the five P-selectin SNPs were comparable between patients and controls, except for −2123G/G genotype which was more frequent in cases. The 715Pro allele was present at lower frequency in Tunisians than in Europeans, and was not protective of CHD. Linkage disequilibrium was seen between −1969G/A, and both Ser290Asn and Asn562Asp. Five-loci haplotype analysis did not identify any CHD-protective or CHD-susceptible haplotypes. To our knowledge, this was the first case-control study to be performed on an Arab/North-African population, and demonstrates that none of the five P-selectin polymorphisms investigated influence CHD susceptibility in Tunisian Arabs.     

The intracellular renin-angiotensin system in the heart

Recently, several novel aspects of the renin-angiotensin system (RAS) were described, which potentially may change the therapeutic strategy to treat cardiovascular disease, in addition to enhancing understanding of this system’s mechanism of action. Most notably, identification of a functional intracellular RAS may address several unanswered questions regarding a direct role of angiotensin (Ang) II in cardiac remodeling and incomplete efficacy of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers or superiority of a renin inhibitor in cardiovascular disorders. We describe the physiology of the intracellular RAS, potential pathologic roles of intracellular Ang II, and the relevance of the intracellular system in view of recent clinical trials involving various RAS inhibitors.     

冠心病患者白细胞介素-1受体拮抗剂基因多态性的研究

目的　探讨白细胞介素 1受体拮抗剂基因 (IL 1RN)内含子 2可变数串联重复多态性(VNTR)和外显子 2 ( + 80 0 6T/C)多态性与冠心病 (CHD)的相关关系 ,以及各基因型对CHD患者血清白细胞介素 1受体拮抗剂 (IL 1Ra)水平的影响。方法　采用聚合酶链反应 (PCR)和PCR RFLP的方法 ,分析 2 4 5例CHD患者和 2 36例健康对照者的IL 1RN(VNTR)和IL 1RN( + 80 0 6T/C)基因型 ,并从CHD患者中随机选择 5 5例 (携带IL 1RN Ⅱ或IL 1RN C者 2 5例 ,不携带者 30例 ) ,利用酶联免疫吸附实验检测其血清IL 1Ra水平。结果　与健康对照组相比 ,不携带IL 1RN Ⅱ或IL 1RN C基因型者患CHD的相对风险度增加 1 91倍 (OR =1 91,95 %CI =1 12～ 3 2 4 ) ;而与心绞痛组相比 ,其患心肌梗死的相对风险度增加 4 15倍 (OR =4 15 ,95 %CI=1 5 0～ 11 4 5 )。携带IL 1RN Ⅱ或IL 1RN C基因型的CHD患者血清IL 1Ra水平显著高于不携带者 (P <0 0 1)。IL 1RN Ⅱ总是伴随着IL 1RN C的出现而出现。结论　IL 1RN(VNTR)和IL 1RN( + 80 0 6T/C)多态间存在完全连锁不平衡 ;其基因型与CHD的发生、发展及该疾病的严重程度密切相关 ;IL 1RN C和IL 1RN Ⅱ可能共同通过促进IL 1Ra的表达而具有保护作用     

瘦素基因启动子G-2548A多态性与冠心病的关系

目的探讨中国湖北地区汉族人群瘦素基因启动子2548编码处碱基G/A多态性与冠心病(CHD)的关系。方法(1)选择CHD患者156例(CHD组),其中急性冠脉综合症80例,稳定性CHD76例,同时入选心电图检查无异常或冠脉造影正常者150例(对照组)。(2)应用聚合酶链反应及限制性片段长度多态性分析技术,分析CHD患者和对照组的瘦素基因型。结果CHD组与对照组中瘦素基因启动子G-2548A编码处A等位基因比较差异有非常显著性(χ2=11.55,P<0.01)。基因型频率的相对危险度分析发现,AA加AG基因型患CHD的危险度是GG基因型的3.827倍(OR=3.827,CI=1.672~8.756)。结论瘦素基因启动子G-2548A的多态性与CHD易感性有关,A等位基因可能是CHD发病的遗传易感因素。     

The renin-angiotensin system in heart failure

The renin-angiotensin aldosterone system does appear to have a central role in the haemodynamic and metabolic response to declining ventricular function. Human heart failure usually occurs in the setting of preceding disease, which may itself influence the underlying activity of the system. Studies of the renin-angiotensin system after myocardial infarction are in agreement with animal models, that transient activation of the renin-angiotensin system occurs. This may be sustained if the cardiac insult is severe and especially if diuretic therapy is initiated. In those patients in whom the insult is less severe, activity of the renin-angiotensin system wanes. The finding that patients with stable untreated heart failure do not have markedly activated renin-angiotensin systems is not surprising, but correction of the plasma and extracellular volume (for instance with a diuretic) will result in reappearance of activation of these systems. Since the introduction of angiotensin-converting enzyme inhibitors, several new peptides have been discovered (atrial natriuretic peptide, endothelin etc.) that have important effects on cardiovascular function. New potential therapeutic agents with actions on neuroendocrine systems, such as the atrial peptidase inhibitors, angiotensin-II receptor antagonists and renin inhibitors, are on the horizon. Such exciting new discoveries will give as much insight into the pathophysiology of heart failure as the angiotensin-converting enzyme inhibitors have done.     

载脂蛋白B等位基因变异与早发冠心病的关系

目的　研究载脂蛋白 B基因 3 '端 VNTR遗传多态性与早发冠心病之间关系。方法　对 60例早发冠心病患者( CHD)和 5 0例正常对照者 (对照组 )全血 DNA采用聚合酶链反应 ( PCR)法扩增载脂蛋白 B( apolipoprotein B)基因 3 '端可变数目串连重复位点 ( variable num ber tandem ly repeated loci- VNTR)多态性。结果　在 110例中 ,各组的 apo B基因位点呈现了不同的基因带型 ,扩增片段大小为 45 0～ 90 0之间。早发冠心病组发现有 12个等位基因 ,正常人群组有15个等位基因。apo B3 ' 端 VNTR的基因频率分布为 0 .0 0 5～ 0 .3 0 83 ,杂合度为 79.0 %～ 88.8%。早发冠心病组中 ,63 0 bp、660 bp等位基因的频率显著高于正常对照组 ,其血脂水平与对照组有显著性差异 ;不同等位基因组中血脂水平差异无显著性。结论　载脂蛋白 B等位基因 63 0 bp、660 bp可能是早发冠心病的一个危险因子     

Research progress of the relationship between angiotensinogen gene polymorphisms and coronary heart disease

Coronary heart disease (CHD) is a major health problem in many countries and its pathogenesis is not yet fully understood, contributing to significant morbidity and mortality. Accumulated evidence manifest clearly that CHD is determined by a complex interplay of genetic and environmental factors. Many clinical data have showed that the renin-angiotensin system (RAS) involved in many cardiovascular diseases, such as hypertension and CHD. Angiotensinogen (AGT) is the key components of the RAS system, and two gene polymorphisms of AGT had been detected of the CHD risk: M235T and T174M. This article reviews the effects of AGT gene polymorphisms on the CHD.     

冠心病病变范围与载脂蛋白E基因多态性及血脂分布的关系

目的 :探讨冠心病 (CHD)病变范围与载脂蛋白E(apoE)基因多态性及血脂分布的关系。 方法 :用酚氯仿抽提核酸法从凝血块中分离DNA ,用多聚酶链式反应 限制性片段长度多态性 (PCR RFLP)方法对新疆乌鲁木齐地区维、汉两民族人群中 10 2例CHD患者和 5 1例对照组人群进行apoE基因多态性 (由ε2、ε3和ε4决定的E2 / 2、E3/ 3、E4 / 4、E4 / 2、E4 / 3和E3/ 2 )HhaI酶切研究。结果 :①CHD组apoE之ε2 ,ε3和ε4等位基因频率分别为 0 .0 735± 0 .2 15 7,0 .774 5± 0 .3117和 0 .15 2 0± 0 .2 4 16 ,1支病变组apoE之ε2 ,ε3和ε4等位基因频率分别为 0 .10 6 1± 0 .2 4 2 3,0 .75 76± 0 .35 6 2和 0 .136 4± 0 .2 2 6 1,2支病变组apoE之ε2 ,ε3和ε4等位基因频率分别为 0 .0 5 5 6± 0 .1992 ,0 .80 5 6± 0 .2 995和 0 .1389± 0 .2 5 6 7,3支病变组apoE之ε2 ,ε3和ε4等位基因频率分别为 0 .0 6 0 6± 0 .2 0 76 ,0 .75 76± 0 .2 82 9和 0 .1818± 0 .2 4 4 3,与正常对照组 (0 .196 1± 0 .30 13,0 .6 6 6 7±0 .36 97和 0 .1373± 0 .2 2 5 4 )比较 ,ε2明显减低 (P <0 .0 5 ) ,病变范围越大 ,ε2越低 ,但病变范围大小之间统计学无差异 ,ε3和ε4随着病变范围增大逐渐升高但统计学无显著差别 (P >0     

Interactions between the renin-angiotensin system and dyslipidemia: relevance in the therapy of hypertension and coronary heart disease

Dyslipidemia and hypertension are frequently observed in patients with ischemic heart disease. Studies from a number of laboratories suggest up-regulation of different components of the renin-angiotensin system (RAS) in patients with hypertension and atherosclerosis. Lipid accumulation in the blood vessels enhances the expression of RAS components; on the other hand, activation of RAS stimulates accumulation of low-density lipoproteins, particularly the oxidatively modified form, in the blood vessels. This concept of cross-talk between dyslipidemia and RAS activation has been proven in laboratory-based studies. Clinical trials also suggest that blockade of dyslipidemia and RAS may have a synergistic salutary effect on the outcome of patients with hypertension and/or manifestations of atherosclerosis. This concept needs to be evaluated in large clinical studies.     

Common genetic polymorphisms and coronary heart disease

Susceptibility to coronary heart disease (CHD) is to some extent genetically determined, but despite a great deal of effort, in the past decade research has shown little progress towards identifying the genetic variants responsible. This article explores the reasons why this is so, using the ACE insertion/deletion polymorphism, which has been the most extensively studied of all genetic polymorphisms with respect to CHD risk, as an example. It is suggested that issues long recognized as important in epidemiological studies of classical risk factors, such as appropriate sample size, a requirement for high levels of statistical significance, and avoidance of excessive subgroup analysis, have tended to be under-appreciated in case-control studies of genetic polymorphisms and disease thus far. I discuss the consequences of such methodological limitations. Finally, I present a ;;checklist' of important factors in study design and analysis in order to assist readers who may be unfamiliar with aspects of genetic methodology in the evaluation of these increasingly frequently conducted studies.