Angiotensinogen T174M and M235T gene polymorphisms are associated with the extent of coronary atherosclerosis.

BACKGROUND: The relations of the angiotensinogen (AGT) T174M and M235T gene polymorphisms to the risk of coronary heart disease (CHD) have been investigated in only a few studies with conflicting results. RESULTS: Therefore, we analysed the relationship of the AGT gene polymorphisms to the presence and extent of CHD in 2250 male Caucasians whose coronary anatomy was defined by means of coronary angiography. The relative frequencies of the T and M alleles of the T174M and of the M235T gene variation did not significantly differ between patients without or with single-, double- or triple-vessel disease and between subjects without or with myocardial infarction (MI). In contrast the mean CHD score--defined by Gensini--was higher within MM homozygotes of the T174M gene variation than within TT genotypes; TM subjects had intermediate values. In M235T genotypes, mean CHD scores were similar in the total sample and in older individuals (> or = 62 years), whereas in younger individuals (< 62 years) a higher CHD score was found within AGT 235 T allele carriers than within MM homozygotes. In younger individuals with high apoAI plasma levels, the mean CHD score was clearly higher within TT homozygotes of the M235T gene variation than within MM genotypes; MT subjects had intermediate values. An interaction between both angiotensinogen gene polymorphisms on the extent of CHD or on the risk of non-fatal MI were not observed when the M allele of AGT T174M was combined either with the T allele or the TT genotype of M235T. CONCLUSIONS: The present study strengthens the hypothesis of an association of both angiotensinogen gene polymorphisms with the extent of coronary heart disease.     

Angiotensinogen M235T and T174M gene polymorphisms in combination doubles the risk of mortality in heart failure

Angiotensinogen M235T and T174M polymorphisms have individually been associated with elevated levels of plasma angiotensinogen, hypertension, and left ventricular hypertrophy. In this study, heart failure patients (n=451) were genotyped for the angiotensinogen M235T and T174M polymorphisms to investigate association with survival (recorded over 4 years of follow-up) and prognostic hormone markers. Patients carrying the 235TT genotype (n=86) were 3 years younger at admission (P=0.011), and, in those with hypertension, diagnosis was made approximately 10 years earlier than other patients. Patients carrying >or=1 174M allele (n=94) were more likely to have a previous history of heart failure (P=0.044) and increased mortality during follow-up (risk ratio: 1.69, 95% CI: 1.03 to 2.79; P=0.038) compared with 174TT homozygotes (n=355), despite having a higher left ventricular ejection fraction (P=0.009). "High-risk" genotype combinations (defined a priori as 235TT and/or >or=1 174M allele; n=144; 32%) were independently predictive of mortality, conferring a 2-fold greater risk of dying during the follow-up period (odds ratio: 2.0; 95% CI: 1.3 to 3.0; P=0.001). This study suggested that angiotensinogen gene variants M235T and T174M may provide prognostic information for long-term survival in heart failure patients.     

血管紧张素原基因M235T多态性与心血管疾病

近年来,越来越多的研究结果表明血管紧张素原基因M235T多态性与心血管疾病密切相关,通过对二者关系的研究,我们可以从分子水平上探讨心血管疾病的病因,从而为心血管疾病的防治提供新的思路。现对这一研究现状作一综述。     

血管紧张素原基因M235T分子变异与原发性高血压的关系

目的：探讨血管紧张素原（ＡＧＴ）基因Ｍ２３５Ｔ分子变异与中国人原发性高血压的关系。　　方法：对８９ 例原发性高血压（原发性高血压组）及９１ 例正常者（正常对照组）用多聚酶链式反应法及限制性片段长度多态性技术对ＡＧＴ基因Ｍ２３５Ｔ多态性进行了检测。　　结果：原发性高血压组Ｔ等位基因频率０．８０,ＴＴ基因型频率０．６７,与正常对照组（０．６６,０．４３）比较有显著性差异,（Ｐ＝ ０．０２３,Ｐ＝ ０．００４）;ＴＴ基因型较ＭＴ＋ ＭＭ 基因型对原发性高血压的比值比为２．７６（９５％ 可信区间为１．５０～５．０６,Ｐ＝ ０．００１）。　　结论：ＡＧＴ基因ＴＴ基因型可能与中国人群原发性高血压发病有关联。     

Angiotensinogen T174M and M235T variants, sodium intake and hypertension among non-drinking, lean Japanese men and women

OBJECTIVE: To examine the interaction of sodium intake with genetic variations of the angiotensinogen gene and hypertension. DESIGN: A community-based case-reference study. SETTING: Two rural Japanese communities. PARTICIPANTS: Non-overweight and non-drinking Japanese men and women: 229 hypertensives and 229 age-, sex- and community-matched normotensives aged 32 to 83 years. METHODS: Polymorphisms of the angiotensinogen gene detected by an allele-specific polymerase chain reaction. A priori hypothesis is individuals with 174M (threonine-to-methionine substitution) or 235T (methionine-to-threonine substitution) allelic variations may have an elevated risk of hypertension when they have a high sodium intake, estimated by 24-h urine collection and a dietary questionnaire. RESULTS: The genotypic frequency of the haplotype including both the 174M and 235T alleles was higher among hypertensives than among normotensives (23 versus 14%, P= 0.02). The frequency of the 174M allele was specifically higher among hypertensives than normotensives (12 versus 7%, P=0.01), and the odds ratio of hypertension associated with the 174M (versus 174T) allele was 1.8 [95% confidence interval (CI) 1.1-3.0, P=0.01]. The frequency of the 235T allele did not vary between the two groups (80 versus 82%, P= 0.40). The relationship between the 174M allele and hypertension was more evident among persons who had higher urinary sodium excretion (> = 166 mmol/day) than those with lower excretion (< 166 mmol/day): odds ratio 2.5 (95% CI, 1.2-5.2), P=0.01 versus 1.5 (95% CI, 0.7-3.1), P= 0.31; P for interaction = 0.04, and this trend was primarily observed for early-onset hypertension (< 55 years at onset). A similar but nonsignificant association was observed when stratified using present and past sodium intake scores derived from questionnaires. CONCLUSION: Angiotensinogen genotype may affect the development of early-onset hypertension among Japanese, particularly in those who have a high sodium intake.     

Angiotensinogen gene M235T polymorphism predicts left ventricular hypertrophy in endurance athletes.

OBJECTIVES: We studied whether left ventricular mass in athletes associates with polymorphisms in genes encoding components of the renin-angiotensin system. BACKGROUND: Adaptive left ventricular hypertrophy is a feature of the athlete's heart. However, similarly training athletes develop left ventricular mass to a different extent, suggesting that genetic factors may modulate heart size. METHODS: We measured left ventricular mass by echocardiography in 50 male and 30 female elite endurance athletes aged 25 +/- 4 (mean +/- SD) years. Deoxyribonucleic acid samples were prepared for genotyping of angiotensinogen (AGT) gene M235T polymorphism, angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and angiotensin II type 1 receptor (AT1) gene A1166C polymorphism. RESULTS: The AGT gene M235T genotypes were significantly associated with left ventricular mass independently of blood pressure in both genders (p = 0.0036 for pooled data). TT homozygotes had greater mass compared with MM homozygotes in both men (147 +/- 12 g/m vs. 132 +/- 15 g/m, p = 0.032) and women (121 +/- 12 g/m vs. 101 +/- 13 g/m, p = 0.019). There was a gender difference in the relation between myocardial mass and AGT genotype, MT heterozygotes resembling MM homozygotes among women and TT homozygotes among men. The other studied gene polymorphisms were not associated with left ventricular mass. CONCLUSIONS: Angiotensinogen gene M235T polymorphism is associated with the variability in left ventricular hypertrophy induced by endurance training, with athletes homozygous for the T allele having the largest hearts. We found no association between ACE gene I/D or AT1 gene A1166C polymorphisms and left ventricular mass.     

Angiotensinogen M235T polymorphism and left ventricular indices in treated hypertensive patients with normal coronary arteries.

OBJECTIVE: Hypertension and left ventricular hypertrophy (LVH) are important causes of morbidity and mortality in the population. Angiotensinogen (AGT) M235T polymorphism has been associated with LVH, left ventricular dimensions, coronary artery disease and antihypertensive drug response in previous studies. We examined relationship between AGT M235T polymorphism and echocardiographic left ventricular indices in a Turkish population of treated hypertensive patients with normal coronary arteries. METHODS: In this cross-sectional study a Turkish population of 92 hypertensive patients treated in our outpatient clinic were enrolled. All patients had normal coronary angiographic examinations. Genotypes for AGT M235T were determined from peripheral leukocytes. Left ventricular dimensions, mass and function indices, after adjustment for clinical covariates were analyzed by multiple regression analysis according to genotypes. RESULTS: Genotype frequencies for AGT M235T were MM-24.7%, MT-52.8% and TT-22.5%. Left ventricular end-systolic (LVES) dimensions for AGT M235T MM, MT, TT genotypes were 17.9+/-4.2 mm, 19.4+/-6.2 mm, and 16.4+/-2.9 mm, respectively (p=0.08). Angiotensinogen M235T TT genotype showed a trend towards a lower LVES dimension but results were not statistically significant. Left ventricular ejection fractions for AGT M235T MM, MT, TT subgroups were 61.3+/-15.0%, 59.4+/-14.0%, and 67.8+/-8.5%, respectively (p=0.07). Angiotensinogen M235T TT genotype showed a tendency towards lower left ventricular mass index but results were not statistically significant. None of the AGT M235T genotypes predicted left ventricular dilatation, mass or function in treated hypertensive patients with normal coronary arteries. CONCLUSION: Angiotensinogen M235T polymorphism was not useful to predict left ventricular mass, function, hypertrophy or dilatation in a small population of treated Turkish hypertensive patients with normal coronary arteries.     

An association of BMI with A (-6) G,M235T and T174M polymorphisms in angiotensinogen gene in essential hypertension

The aim of the study was to assess the existence of possible associations among frequent polymorphisms in angiotensinogen genes and some of the risk factors for essential hypertension, especially body mass index (BMI) and smoking. A total of 192 control subjects (aged 45.87 +/- 3.0 years) and 206 patients with the essential hypertension (aged 48.71 +/- 8.42 years) were compared at three angiotensinogen gene polymorphisms by considering BMI and smoking status. No significant differences in genotype and/or allelic distribution for either A (-6) G ATG, M235T or T174M polymorphisms between the hypertensive and control groups were proved. Significantly more hypertensives than control persons with BMI above 25 kg/m(2) were observed (P(corr) = 0.009), independently on sex distribution. A percentage of 44.6% of smokers in the control group vs 46.0% of smokers in the hypertensive groups were found. No significant difference in concurrence of BMI above 25 kg/m(2) and positive smoking status between control and hypertensive subjects was found. Statistically significant differences were found between control and hypertensive subjects when compared distributions of subjects with certain genotypes of the three examined polymorphisms considering BMI (P(corr) = 0.0002 for AA+AG of A (-6) G ATG, P(corr) = 0.01 for CC + CT of T(174)M ATG and P(corr) = 0.01 for MT + TT of M235T ATG). No functional relationship among obesity and the examined polymorphisms in vivo are known. We conclude that a different distribution of BMI could influence the results of analyses of angiotensinogen gene polymorphisms in essential hypertension-control studies.     

Associations of the Angiotensinogen Gene (M235T, T174M) and the Angiotensin I-Converting Enzyme Gene (I/D) with Blood Pressure in Japanese Workers

Blood pressure may be influenced by several polymorphisms associated with hypertension, such as the angiotensinogen gene (M235T, T174M) and the angiotensin I-converting enzyme gene (I/D). We investigated the associations of these polymorphisms with blood pressure and components of the renin-angiotensin system in Japanese workers. Additionally, we examined whether the polymorphisms were independently associated with blood pressure when other factors were taken into consideration in a general linear model. The study population, which was entirely Japanese, consisted of 196 male subjects. Subjects were selected from workers who received a company health examination.Systolic blood pressure of the M235T MM genotype was significantly higher than that of the MT genotype. Diastolic blood pressure of the M235T MM genotype was significantly higher than that of the MT or TT genotypes. Serum ACE activity of the ACE II genotype was significantly lower than that of the ID or DD genotypes. Multivariate analysis using a general linear model, including age and body mass index, demonstrated that the M235T MM genotype was one of the independent factors affecting blood pressure. The present study demonstrated that the M235T MM genotype was independently associated with systolic blood pressure and diastolic blood pressure in Japanese male workers.     

Angiotensinogen M235T variant and salt sensitivity in young normotensive Caucasians.

BACKGROUND AND AIMS: A single-nucleotide variant of the angiotensinogen gene (AGT 235T) has been associated with essential hypertension and increased plasma levels of angiotensinogen. This variant may also serve as a genetic marker for the increased blood pressure response to dietary salt intake, but the relationship between AGT genotype and salt sensitivity has not been studied until now. We therefore examined the relationship between the AGT 235T genotype and the blood pressure response to short-term dietary salt restriction in young normotensive men. SUBJECTS AND METHODS: A total of 187 young normotensive men were characterized for family history of hypertension, salt sensitivity, plasma parameters of the renin-angiotensin system under high- and low-salt diets, and the AGT 235T genotype. RESULTS: While the T allele was significantly associated with a positive family history of hypertension (chi2 = 7.0; P< 0.03) and higher plasma angiotensinogen levels (P< 0.015) and renin activity (P < 0.037), blood pressure under both diets was not significantly affected by the AGT genotype. When the subjects were classified into salt-resistant and salt-sensitive groups, genotypic distribution was nearly identical between both groups (frequency of T allele: 0.45 versus 0.46). CONCLUSION: Our findings demonstrate that the AGT 235T allele is significantly associated with a positive family history of hypertension, but is not an important determinant of the blood pressure response to dietary salt intake in young normotensive subjects. It is therefore unlikely that the AGT 235T genotype can serve as an early genetic marker of salt sensitivity.     

家族性原发性高血压与血管紧张素原基因M235T突变关系的研究

目的：探讨血管紧张素原基因Ｍ２３５Ｔ突变与家族性原发性高血压（ＥＨ）的关系。　　方法：应用脱氧核糖核酸（ＤＮＡ）杂交和测序检定方法,对一个典型原发性高血压大家系１００名成员［分直系亲属高血压组（ｎ＝ ４５）、直系亲属正常血压组（ｎ＝ ３８）及非直系亲属正常血压组（ｎ＝ １７）］和正常血压对照家系直系亲属２１ 名（为正常对照组）成员按＜ ３５岁和≥３５岁２个年龄层的Ｍ２３５Ｔ突变进行分析。　　结果：比较４组在＜ ３５ 岁和≥３５ 岁２个年龄层的Ｍ２３５Ｔ分布。表明各年龄层中,４组间Ｍ２３５Ｔ基因型及基因频率分布未见显著不同。　　结论：血管紧张素原基因Ｍ２３５Ｔ突变与该家族性原发性高血压没有显著关联;Ｍ２３５Ｔ突变可能不是该家族性原发性高血压的遗传易感因素。     

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。     

血管紧张素原基因T174M和血管紧张素转换酶基因I/D多态性与急性心肌梗死的相关性

目的探讨中国汉族人群血管紧张素转换酶和血管紧张素原基因型的分布及其与急性心肌梗死的关系。方法应用聚合酶链反应技术,对112例急性心肌梗死患者、128例非冠心病患者血管紧张素转换酶I/D多态性及血管紧张素原T174M多态性进行检测。结果血管紧张素转换酶基因型分布及等位基因频率在病例组及对照组间差异有显著性(P<0.01)。病例组和对照组血管紧张素原基因型及等位基因频率总体分布差异亦有显著性(P<0.05)。联合基因分析显示,急性心肌梗死组血管紧张素转换酶DD基因型 血管紧张素原174MM基因型频率显著高于对照组(P<0.01),具有该联合基因型者发生冠心病的风险比数比(OR=8.467)明显高于单独具有血管紧张素转换酶DD基因型(OR=2.558)或血管紧张素原174MM基因型(OR=6.176)者。结论血管紧张素原T174M基因多态性中M等位基因和血管紧张素转换酶I/D基因多态性基因中的D等位基因是中国汉族人群冠心病发病的危险因素之一。同时具有血管紧张素转换酶DD型及血管紧张素原174MM型发生冠心病的相对风险显著高于单基因血管紧张素转换酶DD型及单基因血管紧张素原174MM型。     

血管紧张素原基因T174M多态性与新疆维吾尔族心肌梗死的相关性研究

目的心肌梗死病因复杂，目前认为其发病是个体基因和环境因素共同作用的结果，本研究旨在探讨血管紧张素原基因T174M多态性与新疆维吾尔族心肌梗死的相关性。方法采用聚合酶链反应－限制性片段长度多态性方法，对175例心肌梗死患者和170例健康受试者血管紧张素原基因T174M进行分析，同时进行血压和血生化水平检测。结果血管紧张素原基因T174M在病例组和健康对照组中基因型频率分别为：TT型69．71％和74．70％，TM型17．14％和20．00％，MM型13．14％和6．30％，两组MM基因型差异具有统计学意义（P〈0．05），且病例组M等位基因频率高于对照组（P〈0．01），而TM和TT基因型差异无统计学意义（P〉0．05）。结论血管紧张素原基因T174M基因多态性与心肌梗死的发生具有相关性，MM基因型和M等位基因可增加新疆维吾尔族人群心肌梗死发生的风险。     

Relationship between the M235T and G(-6)A polymorphisms of the angiotensinogen gene

AIMS: Previous studies have reported tight linkage disequilibrium between the T235 and the A(-6) molecular variants of the angiotensinogen gene. This study was designed primarily to ascertain whether a similar relationship exists between the M235 and the G(-6) variants of the gene. We have investigated the degree of agreement between the genotypes of the M235T and the G(-6)A polymorphisms in two ethnic groups. METHODS: Subjects were an heterogeneous group of normotensive and hypertensive subjects of Caucasian (n = 77) and Afro-Caribbean (n = 51) origin. DNA was extracted from whole blood and was genotyped for both the M235T and G(-6)A polymorphisms using PCR-based methods. RESULTS: The distribution frequencies of the MM, MT, and TT genotypes were 0.39, 0.42, and 0.20 in white subjects, and 0.09, 0.17, and 0.74 in black subjects, respectively (chi-square, P < 0.0001). The distribution of AA, GA, and GG genotypes also differed between the two groups as follows: 0.22, 0.48, and 0.30 in white subjects, and 0.82 and 0.18 and 0 in black subjects respectively (chi-square, P < 0.0001). The agreement for TT-AA, MT-GA, and MM-GG was 93%, 91%, and 76% respectively in white and 100%, 67% and 0% respectively in black subjects. CONCLUSIONS: The results indicate ethnic differences in the distribution of both M235T and G(-6)A genotypes. The trend towards a decrease in the degree of agreement in the order of TT-AA > MT-GA > MM-GG suggests that linkage disequilibrium between the M235 and G-6 variant does not mirror that observed with the T235 and A-6 variants. These observations may have significant implications regarding the associations between the G(-6)A polymorphism and hypertension. However, this needs to be further investigated.     

检测血管紧张素原基因M235T多态性的两种方法比较

目的对用于检测血管紧张素原基因M235T多态性的突变基因分离聚合酶链反应法(MS-PCR)和聚合酶链反应-限制性片段长度多态性分析法(PCR-RFLP)进行比较.方法分别用MS-PCR和PCR-RFLP检测82例住院患者的基因型及等位基因频率,并进行比较.并将用这两种方法测得的T等位基因发生频率与当地人群的总体发生率分别进行比较.结果两种方法所测得的AGT基因型分布及等位基因发生频率差异均有统计学意义(P＜0.01),T等位基因发生率分别为0.87、0.71,后者更符合亚洲及我国人群(0.63～0.79;0.63～0.82).结论在建立了最佳实验体系的前提下,选择传统的PCR-RFLP结果更加可靠.     

Angiotensinogen gene T174M polymorphism: opposite relationships with essential hypertension and obesity in a homogeneous population from Majorca (Baleric Islands, Spain)

Numerous association studies have been performed to evaluate the relationship between the angiotensinogen gene and the essential hypertension, but their results are conflicting. The conflicting results may be explained by methodological reasons, particularly genetic differences in the population samples, phenotypic differences in the hypertensive populations analyzed, lack of appropriate control for other hypertension risk factors in some studies, or limited statistical power among many studies. Furthermore, hypertension is a public health issue of great relevance in Baleric Islands (Spain). For these reasons we performed an association study about the relationship between the M235T, T174M and G-6A diallelic polymorphisms of the angiotensinogen gene and hypertension in a population from Majorca (Balearic Islands), in which a considerable homogeneity with respect to ethnicity and environmental factors could be documented. This population was composed of 109 patients and 107 controls. Alleles of the angiotensinogen gene were determined by PCR and restriction site polymorphism analysis. The different genotypes were tested for association with dependent variables by univariate and multivariate logistic regression analysis. In the univariate analysis we found no evidence of association between the angiotensinogen gene genotypes and hypertension. This lack of association was independent of obesity, familial history of hypertension and diabetes for the genotypes of the polymorphisms M235T and G-6A; however, in the multivariate analysis the T174T174 genotype showed an almost significant positive association with hypertension [OR = 2.76 (95% confidence interval: 1.00-7.65, p = 0.05)]. The T174T174 genotype also showed a significant negative association with obesity [OR = 0.41 (95% confidence interval: 0.18-0.90, p = 0.03)] that remained after adjustment by sex, hypertension and diabetes [OR = 0.26 (95% confidence interval: 0.10-0.65, p = 0.004)]. Our results: a) are in contrast with the results from most previous studies that found a relationship of the T174M polymorphism with hypertension, as in those studies the M174 allele was responsible for the association; b) emphasize the need for rigorous control for obsesity in the studies of association between the angiotensinogen gene and hypertension; c) underscore the importance and the utility of using concrete populations to carry out studies on the genetic dissection of hypertension.