M235T Gene Research Articles

Effects of the angiotensinogen gene M235T and A(-6)G variants on blood pressure and other vascular risk factors in a Spanish population.

Angiotensinogen (AGT) gene polymorphism has shown significant differences in the allelic frequencies between hypertensive and normotensive subjects. This allele frequency varies among ethnic groups. There are still some controversies related to the 235T-variant as a marker for essential hypertension. As part of an extensive case-control study carried out in a Spanish population, we selected the 237 subjects with a diagnosis of essential hypertension according to the established criteria. A group of 242 normotensives matched for age and gender was used as control. Smoking habits, a previous diabetes and hypertension medical history, body mass index (BMI) and blood pressure (BP) values were recorded. Glucose, plasma creatinine, lipid profile with Lp(a), homocysteine and microalbuminuria were measured. Angiotensinogen M235T-gene polymorphism was determined by polymerase chain reaction (PCR) from genomic DNA. A(-6)G polymorphism was determined by mutagenically separated PCR (MS-PCR). BP values, BMI and microalbuminuria were significantly higher in hypertensive subjects; 31.6% of hypertensives and 40.1% normotensives were active smokers. M235T-genotype frequencies were not different in the hypertensive and normotensive population. Similarly, homocigotic AA predominate in the hypertensives but without statistical significance. The association of 235T-genotype or the changes in the promoter activity due to A(-6) substitution with essential hypertension was not confirmed in the multivariate regression analyses. Only a previous family history of hypertension and BMI were significantly associated with hypertension. Journal of Human Hypertension (2000) 14, 789-793

The angiotensinogen gene 235T variant is associated with an increased risk of restenosis after percutaneous transluminal coronary angioplasty

The therapeutic benefit of percutaneous transluminal coronary angioplasty (PTCA) is limited by restenosis in 30-40% of patients. The underlying mechanisms are currently not well understood. Besides clinical and angiographic variables, genetic factors may be involved. In the present study, we investigated the associations between the angiotensinogen T174M and M235T, the angiotensin I-converting enzyme (ACE) I/D and the angiotensin II type 1 receptor A1166C gene polymorphisms and restenosis in 511 patients who had undergone successful PTCA (without stenting) and follow-up angiography. Clinical and angiographic variables were also considered as possible predictors of restenosis. Stenosis severity was estimated by visual inspection of the angiograms. Altogether, 160 patients had restenosis, as defined by a greater than 50% reduction in the diameter of the dilated segment at follow-up angiography compared with the findings immediately following angioplasty. There were significantly more carriers of the angiotensinogen 235T allele and more patients with the ACE DD genotype in the restenosis group than in the no restenosis group, but only the angiotensinogen 235T allele (and not the ACE DD genotype) remained significantly associated with restenosis following multifactorial analyses. No differences between the two groups were found with respect to the other gene polymorphisms. Patients who subsequently developed restenosis had a higher degree of stenosis and more severe lesions before PTCA, as well as less residual stenosis immediately after PTCA. We conclude that the angiotensinogen M235T gene polymorphism may be an independent predictor of restenosis after PTCA.

Genes and diabetic nephropathy: what have we learnt so far?

Genes and diabetic nephropathy: what have we learnt so far?

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 (≥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 gene M235T polymorphism predicts left ventricular hypertrophy in endurance athletes

OBJECTIVESWe studied whether left ventricular mass in athletes associates with polymorphisms in genes encoding components of the renin–angiotensin system.BACKGROUNDAdaptive 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.METHODSWe 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.RESULTSThe 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.CONCLUSIONSAngiotensinogen 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.

The p22 phox A640G gene polymorphism but not the C242T gene variation is associated with coronary heart disease in younger individuals

Background. Most recently, evidence has been presented that the NADH/NADPH oxidase p22 phox C242T, but not the A640G gene polymorphism is associated with a reduced risk of coronary artery disease (CAD). Methods and results. We analysed the relationships of both p22 phox gene polymorphisms to CAD in 2205 male Caucasians whose coronary anatomy was defined by means of coronary angiography. In the total population and in high and low risk groups the relative frequencies of the C242T alleles were essentially the same in patients without or with CAD and in individuals without or with myocardial infarction. In contrast, the G allele of the A640G polymorphism was significantly more frequent in subjects without CAD than in patients with CAD (Odds ratio (OR) 0.74 (0.57−0.98); P=0.038 in multiple logistic regression (MLR)). Correspondingly, the AA genotype of A640G was preferentially found in patients with CAD. These associations did not disappear when the analyses were corrected for multiple comparisons for other gene polymorphisms (ACE I/D gene variation, angiotensinogen T174M and M235T gene polymorphisms, AT1 receptor gene variation, phox C242T gene polymorphism, paraoxonase PON54 and PON191 gene variations) (2p=0.01 in MLR for the presence of CAD; 2p=0.039 in multiple regression for the extent of CAD). The association of the A640G gene variation with the presence and extent of CAD was not only identified in the total sample, but was even stronger in various high risk subpopulations of younger individuals (e.g. with hypertension with or without increased apolipoprotein B plasma levels). Conclusions. Our observations allow the assumption that the p22 phox A640G gene polymorphism is independently associated with the presence and extent of coronary artery disease.

Lack of association of angiotensin-converting enzyme (DD/II) and angiotensinogen M235T gene polymorphism with renal function among Chinese patients with type II diabetes.

The prevalence of diabetic nephropathy is greater in nonwhite patients with type II diabetes, including the Chinese, and genetic variation appears to have a role. We examined angiotensin-converting enzyme (ACE) DD/II and angiotensinogen (Atg) M235T polymorphism in a cohort of Chinese patients with type II diabetes with an average duration of diabetes of 14 years. Group A (n = 88) did not have significant diabetic nephropathy (creatinine levels </= 130 micromol/L [</=1.48 mg/L], without macroalbuminuria), and group B (n = 80) had significant diabetic nephropathy (macroalbuminuria or creatinine level >130 micromol/L [>1.48 mg/d], and those undergoing dialysis). The two groups were matched in different aspects, including age, duration of diabetes, blood pressure, and glycemic control. The results showed: (1) no difference of genotype distribution between groups A and B (DD:DI:II, 14%:45%:41% v 8%:38%:54%; P = 0.20; TT:TM/MM, 70%:30% v 76%:24%; P = 0.43), (2) no evidence of synergistic effect of ACE (DD/II) and Atg M235T gene polymorphisms, (3) no difference of allele frequencies between groups A and B (D:I, 36%:64% v 27%:73%; P = 0.20 and T:M, 86%:16% v 86%:14%; P = 0.73), and (4) ACE activity was greatest in patients with DD genotype and least in those with II genotype (DD:DI:II = 66. 9 +/- 13.3 U/L:61.5 +/- 19.9 U/L:45.0 +/- 17.0 U/L; P < 0.005). The data do not support a role of ACE (DD/II) or Atg M235T polymorphism in the development of diabetic nephropathy in Chinese patients with type II diabetes, and no synergistic effect was found between them. Greater ACE activity was associated with DD genotype, and its role in diabetic nephropathy remains to be elucidated.

Influence of gene polymorphisms of the renin-angiotensin system on clinical outcome in heart failure among the Chinese

Background An association between the DD allele of the angiotensin-converting enzyme gene and a poorer outcome in patients with heart failure has been found in whites. The DD allele frequency is lower in Chinese, but the M235T variant of the angiotensinogen gene is more common in Chinese than whites; it is not known to what extent polymorphisms of the renin-angiotensin system affect clinical status or prognosis in Chinese patients with heart failure. Methods We assessed the relations among polymorphism of the angiotensin-converting enzyme gene, angiotensinogen M235T (AGT) gene, and angiotensin type I receptor A1166C gene with left ventricular systolic function, left and right ventricular diastolic function, serum angiotensin-converting enzyme, plasma aldosterone and atrial natriuretic peptide levels at presentation, and clinical outcome at 1 year (survival, hospital admissions) in a cohort of Chinese patients with typical systolic heart failure (n = 82). Results We confirmed the low prevalence of the angiotensin-converting DD and the angiotensin type I receptor CC genotypes, and high prevalence of the AGT TT genotype in Chinese subjects compared with whites. There was no relation between the various gene polymorphisms and survival at 1 year assessed by multiple regression or Cox regression survival analysis. The AC variant of the angiotensin type I receptor gene was associated with morbidity over a 1-year period (hospital admissions) and increased baseline aldosterone levels, but none of the other polymorphisms correlated with systolic or diastolic function, aldosterone or atrial natriuretic peptide levels. By multiple regression for effects on mortality rate, only atrial natriuretic peptide and age were significant. Conclusions In Chinese patients with heart failure, polymorphisms of the renin-angiotensin system do not appear to be related to survival or severity, probably because of the different prevalence of these genotypes in the Chinese. Thus this study illustrates that large interethnic differences in the frequencies of genotype polymorphisms of the renin-angiotensin system exist and results from one ethnic group cannot be extrapolated to another. (Am Heart J 1999;137:653-7.)

Angiotensinogen M235T polymorphism is associated with plasma angiotensinogen and cardiovascular disease

Background Genes encoding components of the renin-angiotensin system have been associated with elevated blood pressure (BP) and an increased risk of coronary artery disease. To explore the role of the angiotensinogen (AGT) gene in coronary atherosclerosis and thrombosis, we studied the effect of the AGT M235T gene variant on plasma AGT levels and BP in patients with coronary artery disease and in the subgroup of survivors of myocardial infarction as compared with angiographically defined control subjects. Methods and Results This was a case-control study of 301 white male subjects examined at Frankfurt University medical center. Plasma AGT levels increased stepwise according to the number of T235 alleles present (no T235 allele, 14.8 ± 3.9 nmol/L; 1 allele, 15.7 ± 5.1 nmol/L; 2 alleles, 17.3 ± 4.7 nmol/L; P = .006). In a multivariate model, circulating AGT emerged as the most important predictor of diastolic pressure ( P = .001). In addition, AGT M235T gene polymorphism remained a significant predictor of diastolic BP in a multivariate model adjusted for age, body mass index, fasting glucose, apolipoprotein B, presence of coronary artery disease, and treatment with antihypertensive agents ( P < .05). Finally, homozygosity for T235 was associated with increased univariate risk of coronary artery disease and myocardial infarction (odds ratio estimates 1.5; 95% confidence intervals 1.1 to 2.1, P = .03, and 1.0 to 2.1, P = .05, respectively). Conclusions The significant relations observed between the AGT M235T variant, its protein product, and the cardiovascular disease phenotypes provide evidence for a possible role of elevated circulating AGT in the pathogenesis of coronary artery disease. (Am Heart J 1999;137:698-705.)

Angiotensin I converting enzyme and angiotensinogen gene polymorphisms related to 24-h blood pressure in paediatric type I diabetes mellitus.

The aim of this study was to evaluate two putative predictive genetic markers for hypertension in children and adolescents with diabetes mellitus. Ambulatory blood pressure measurements were performed in 199 patients with type I diabetes mellitus (mean age 16.5 years, mean duration of diabetes 7.7 years) and compared to those of 1141 healthy children. The local allele frequencies were established based on a control population consisting of 181 healthy subjects. The allele frequencies of the angiotensinogen gene M235T polymorphism was nearly identical in insulin-dependent diabetes mellitus patients (MM 33%, MT 51%, TT 16%) and controls (MM 35%, MT 49%, TT 16%). In contrast, the genotype distribution of the angiotensin I converting enzyme gene insertion/deletion (I/D) polymorphism was different between patients with type I diabetes mellitus (DD 26%, ID 49%, II 25%) and the control group (DD 37%, ID 44%, II 19%) (P=0.04). Relative nocturnal systolic and diastolic pressures in patients with diabetes were higher than in healthy age- and height-matched controls; no association was found with the angiotensinogen gene M235T polymorphism. Relative nocturnal diastolic blood pressure was higher in patients homozygous for the I allele of the angiotensin I converting enzyme gene. Nocturnal systolic and diastolic blood pressure is higher in patients with type I diabetes than in healthy children. The formerly described, but controversial, association of the M235T polymorphism with arterial hypertension could not be confirmed in this study.

Diabetic nephropathy is associated with AGT polymorphism T235: results of a family-based study.

Diabetic nephropathy is a serious and frequent complication of insulin-dependent diabetes mellitus (IDDM) that has a strong genetic component. Several case-control studies have reported conflicting results with regard to the role of angiotensinogen gene polymorphisms, specifically the M235T T allele, in the development of diabetic nephropathy. The primary limitation of the case-control approach is that bias may be introduced by unrecognized differences in the populations selected for cases and control subjects. In contrast, family-based approaches, such as the transmission/disequilibrium test, assess whether a particular variant, or allele, is transmitted preferentially from a parent having a single copy of that allele. Thus each family provides its own control, thereby eliminating spurious results caused by mismatched population samples. To take advantage of this study design for further investigation of M235T, we collected from the Joslin Diabetes Center in Boston 148 IDDM patients with diabetic nephropathy, 62 nephropathy-free patients with long-duration IDDM, and, very importantly, parents of all these individuals. We found that among males (but not females) the T allele of the M235T polymorphism was transmitted preferentially to those with nephropathy compared with IDDM patients without nephropathy (P=.05). Moreover, the T allele was transmitted preferentially to patients with the most severe manifestation of nephropathy, end-stage renal disease (P=.04). In conclusion, results obtained in our family-based study support a role of the angiotensinogen gene M235T polymorphism, and specifically the T allele, in the development of diabetic nephropathy in IDDM.

Essential hypertension and 5' upstream core promoter region of human angiotensinogen gene.

The angiotensinogen (AGT) gene M235T variant is associated with essential hypertension and elevated plasma AGT concentrations, although the underlying mechanisms are unknown. Recent studies have suggested that AGCE 1 (human AGT gene core promoter element 1) located in the 5' upstream core promoter region (position -25 to -1) of the human AGT gene has an important part in the expression of AGT mRNA by binding with transcription factor AGCF 1 (human AGT gene core promoter element binding factor 1), and a mutation at -20 from adenine to cytosine (A-20C) increases the level of expression of this transcript. We therefore examined subjects with this mutation to study the association with increased plasma AGT concentrations and with essential hypertension. One hundred eighty-eight subjects receiving no antihypertensive medication were examined with regard to the correlation between A-20C and plasma AGT concentrations, and 234 subjects were studied with respect to the association between A-20C and essential hypertension. A-20C was determined by polymerase chain reaction-restriction fragment length polymorphism analysis with EcoOR 109I. Multiple regression analysis showed a weak but significant correlation between A-20C and plasma AGT concentrations (P=.047) and essential hypertension (P=.049). The results suggest that A-20C may underlie the increase in plasma AGT concentrations and be involved in the development of essential hypertension.

Association of the angiotensin I converting enzyme gene deletion polymorphism with early onset of ESRF in PKD1 adult polycystic kidney disease

To determine the effect of the ACE gene insertion/deletion (I/D) polymorphism, angiotensinogen gene M235T polymorphism and the angiotensin 1 receptor gene A1166C polymorphism on the age of onset of end-stage renal failure (ESRF) in PKD1 adult autosomal-dominant polycystic kidney disease (ADPKD), 189 individuals from 46 families with PKD1 were genotyped for each polymorphism. Of the 189 patients 52 (28%) reached ESRF at an average age of 48 +/- 1 year. In patients genotyped for the ACE gene insertion/deletion polymorphism the frequencies of the DD, ID and II genotypes were similar to those expected from Hardy Weinberg equilibrium. In patients with ESRF there was an excess of patients homozygous for the deletion allele (DD: 48% chi2 = 9.97 (1df) P = 0.002). Cumulative renal survival was significantly reduced among those with DD genotype compared to ID and II genotypes. The estimated mean renal survival (95% confidence intervals) were: DD, 52 years [48, 57]; II, 59 years [54, 63]; ID, 64 years [56, 72]; chi2 = 6.13 (1df) P = 0.013, DD versus ID/II. The mean age of renal failure was significantly younger in the DD genotype compared to ID and II genotypes (DD, ID, and II: 44 +/- 2, 49 +/- 2 and 54 +/- 3 years, respectively; P < 0.05 DD vs. ID, P < 0.05 DD vs. II). Ten of the eleven patients who reached ESRF before the age of 40 were homozygous for the deletion allele. The relative risk for ESRF below the age 40 for DD genotype was 17. For all ages there was an overall increased risk of 1.4 for ESRF with the DD genotype. There was no interaction between age of onset of ESRF and either the angiotensinogen M235T allele or angiotensin 1 receptor A1166C polymorphism. This study strongly suggests that PKD 1 patients homozygous for the deletion allele of the ACE gene are at increased risk of developing ESRF at a early age.

Angiotensinogen gene M235T polymorphism is not associated with diabetic nephropathy

There is agreement that a family history of hypertension (HT), is a predictor for the risk of diabetic nephropathy (DN) in patients with type 2 diabetes, and possibly also type 1 diabetes. It follows that genes related to the risk of hypertension must also be considered candidate genes for DN. The 235T allele of the angiotensinogen gene was found to be related to primary HT. To examine whether it is predictive for DN as well, we examined the angiotensinogen gene polymorphism in 230 healthy local controls, 423 patients with type 1 diabetes (n = 180 with DN; n = 243 without DN) and 663 patients with type 2 diabetes (n = 310 with DN; n = 353 without DN). The angiotensinogen gene M235T polymorphism was determined using PCR amplification. The following results were obtained (i) no significant difference of genotype distribution (type 1: MM/MT/TT (%) 27.6/57.2/15.2 vs 27.2/56.1/16.7 (P = 0.92); type 2; MM/MT/TT (%) 31.7/48.2/2/20.1 vs. 32.9/46.8/20.3 (P = 0.93) or allele frequencies (type 1: M 0.56 vs. 0.55 (P = 0.795); type 2; M 0.56 vs. 0.56 (P = 0.86)) was found, between diabetic patients with or without DN, (ii) no difference was found between normotensive and hypertensive diabetic patients. The data argue against a role of the angiotensinogen gene M235T polymorphism in the manifestation of diabetic nephropathy or hypertension in diabetic patients.

Angiotensinogen gene M235T polymorphism is not associated with diabetic nephropathy

Angiotensinogen gene M235T polymorphism is not associated with diabetic nephropathy