angiotensinogen and Coronary-Disease

The angiotensinogen (AGT) gene has been shown to be involved in the development of coronary heart disease (CHD). However, the results have been inconsistent. In this study, the authors performed a meta-analysis to clarify the associations between AGT polymorphisms and CHD risk among the Chinese population.. Published literature from PubMed, the China National Knowledge Infrastructure and Wanfang Data were searched. Pooled odds ratio (OR) and 95% confidence interval (CI) were calculated using a fixed- or random-effects model.. Fourteen studies (2540 cases and 2173 controls) for M235T polymorphism and five studies (655 cases and 815 controls) for T174M polymorphism were included in the meta-analyses. The results showed that M235T polymorphism was significantly associated with CHD risk under a recessive model (OR=1.65, 95% CI 1.22-2.25). There was also significant association between T174M polymorphism and CHD risk under a homogeneous co-dominant model (OR= 4.20, 95% CI 1.90-9.29) and a recessive model (OR=4.15, 95% CI 1.88-9.15). Further sensitivity analyses confirmed the significant association.. The meta-analyses indicated the significant associations of two AGT polymorphisms (M235T, T174M) with CHD risk in the Chinese population.

Topics: Amino Acid Substitution; Angiotensinogen; Asian People; China; Coronary Disease; Genetic Predisposition to Disease; Humans; Polymorphism, Single Nucleotide; Publication Bias

The M235T polymorphism in the AGT gene has been related to an increased risk of hypertension. This finding may also suggest an increased risk of coronary heart disease (CHD).. A case-cohort study was conducted in 1,732 unrelated middle-age women (210 CHD cases and 1,522 controls) from a prospective cohort of 15,236 initially healthy Dutch women. We applied a Cox proportional hazards model to study the association of the polymorphism with acute myocardial infarction (AMI) (n = 71) and CHD. In the case-cohort study, no increased risk for CHD was found under the additive genetic model (hazard ratio [HR] = 1.20; 95% confidence interval [CI], 0.86 to 1.68; P = 0.28). This result was not changed by adjustment (HR = 1.17; 95% CI, 0.83 to 1.64; P = 0.38) nor by using dominant, recessive and pairwise genetic models. Analyses for AMI risk under the additive genetic model also did not show any statistically significant association (crude HR = 1.14; 95% CI, 0.93 to 1.39; P = 0.20). To evaluate the association, a comprehensive systematic review and meta-analysis were undertaken of all studies published up to February 2007 (searched through PubMed/MEDLINE, Web of Science and EMBASE). The meta-analysis (38 studies with 13284 cases and 18722 controls) showed a per-allele odds ratio (OR) of 1.08 (95% CI, 1.01 to 1.15; P = 0.02). Moderate to large levels of heterogeneity were identified between studies. Hardy-Weinberg equilibrium (HWE) violation and the mean age of cases were statistically significant sources of the observed variation. In a stratum of non-HWE violation studies, there was no effect. An asymmetric funnel plot, the Egger's test (P = 0.066), and the Begg-Mazumdar test (P = 0.074) were all suggestive of the presence of publication bias.. The pooled OR of the present meta-analysis, including our own data, presented evidence that there is an increase in the risk of CHD conferred by the M235T variant of the AGT gene. However, the relevance of this weakly positive overall association remains uncertain because it may be due to various residual biases, including HWE-violation and publication biases.

Topics: Angiotensinogen; Case-Control Studies; Cohort Studies; Coronary Disease; Female; Genetic Predisposition to Disease; Humans; Middle Aged; Polymorphism, Genetic; Proportional Hazards Models; Risk Factors

Angiotensinogen, a key protein in the renin-angiotensin system, plays an important role in cardiovascular hemostasis. Many studies have examined the association between polymorphisms in the angiotensinogen gene and risk of coronary heart disease (CHD), but the results have been inconsistent.. We performed a meta-analysis of 43 associations studies on 2 angiotensinogen polymorphisms (M235T and T174M) and risk of CHD published before March 2007, including a total of 13,478 CHD cases and 17,024 controls. We also explored potential sources of heterogeneity. In a combined analysis, the summary per-allele odds ratio for CHD of the M235T polymorphism was 1.11 (95% confidence interval, 1.03 to 1.19). However, when the analyses were restricted to 4 larger studies (n >500 cases), the summary per-allele odds ratio was 0.99 (95% confidence interval, 0.94 to 1.04). Our analyses detected a possibility of publication bias with an overestimate of the true association by smaller studies. A meta-analysis of studies on the 174M variant showed no significant overall association with CHD, yielding a per-allele odds ratio of 1.07 (95% confidence interval, 0.93 to 1.22).. This meta-analysis suggested an overall weak association between the M235T polymorphism and CHD risk. However, the association was not observed in several larger studies, suggesting a publication bias. Additional very large-scale studies are warranted to provide conclusive evidence on the effects of the angiotensinogen gene and other genes within the renin-angiotensin system on risk of CHD.

Topics: Adult; Aged; Alleles; Angiotensinogen; Coronary Disease; Ethnicity; Female; Gene Frequency; Genetic Predisposition to Disease; Haplotypes; Humans; Male; Middle Aged; Mutation, Missense; Point Mutation; Polymorphism, Genetic; Prospective Studies; Publication Bias; Research Design; Retrospective Studies

Since the discovery of renin by Tigerstedt and Bergmann, the renin angiotensin system (RAS) has been recognized as an important modulator of blood pressure and volume homeostasis. Based on these functions a pathophysiological role of the RAS in the pathogenesis of hypertension and other cardiovascular disorders has been postulated. The therapeutic benefit of RAS inhibition by angiotensin converting enzyme (ACE) inhibitors and angiotensin II (ANG II) antagonists in these conditions has been shown. It remains unclear, however, whether the changes in RAS activity associated with cardiovascular disease are primary or secondary factors. It is well known that hypertension and hypertensive end-organ disease is influenced by genetic factors. Gene polymorphisms for virtually all components of the RAS have been described and investigated in clinical studies. It remains to be determined, however, how relevant these findings are for disease etiology. This review, therefore, will attempt to discuss the causal implications of these genetic studies for cardiovascular disease. The role of angiotensinogen and ACE for hypertension, coronary artery disease and other cardiovascular disorders is discussed in this context in an exemplary fashion.

Topics: Angiotensinogen; Animals; Coronary Disease; Genetic Predisposition to Disease; Humans; Hypertension; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Renin-Angiotensin System

The acute myocardial infarction is a multi factor disease, and various risk factors participate in its occurrence and progression. Recently, many investigators have paid their attention to the genetic polymorphisms as new risk factors for coronary artery disease. These include the polymorphisms or mutations of the gene which relates to hypertension, diabetes, the platelet function, the property of the blood vessel, the blood coagulation fibrinogenolysis system, and serum lipids. The tendency toward the occurrence and progression of coronary artery disease might be decided genetically by combining these genetic polymorphisms.

Topics: Angiotensinogen; Apolipoproteins; Blood Coagulation Factors; Coronary Disease; Humans; Mutation; Nitric Oxide; Peptidyl-Dipeptidase A; Platelet Glycoprotein GPIb-IX Complex; Polymorphism, Genetic; Risk Factors

To investigate whether leptin receptor (LEPR) 223A>G polymorphism influences serum lipid levels and whether this polymorphism affects the effectiveness of simvastatin in Chinese patients with coronary heart disease (CHD).. A total of 312 patients with CHD were treated with simvastatin 20 mg/day. Fasting serum lipids were determined before and after 12 weeks of treatment.. Patients with AA genotype had significantly higher total cholesterol (TC) levels and lower high-density lipoprotein cholesterol (HDL-C) levels than those with GG genotype (P < 0.05) before simvastatin treatment. In addition, the ability of simvastatin to increase HDL-C levels was significantly lower in patients with AA genotype than those with GG genotype (P < 0.05).. The 223A>G polymorphism of LEPR significantly modulates the HDL-C response to simvastatin in Chinese patients with CHD.

Topics: Aged; Alleles; Angiotensinogen; Asian People; Coronary Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Genotype; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lipids; Male; Middle Aged; Polymorphism, Genetic; Receptors, Leptin; Simvastatin; Treatment Outcome

We studied the relation between renin-angiotensin system (RAS) related gene polymorphisms, such as angiotensin converting enzyme (ACE) insertion/deletion (I/D), angiotensinogen (AGT) M253T and angiotensin II type 1 receptor (AT1R) A1166C, and the effect of quinapril, an ACE inhibitor with high tissue-binding affinity, on preventing restenosis after percutaneous coronary intervention (PCI). A total of 253 patients successfully treated for coronary artery disease were randomly assigned to quinapril or control. Of the 215 patients who completed the follow-up, we determined gene polymorphisms in 204 patients with 241 lesions who provided blood samples for genotype determination. In the control, the ACE D homozygotes showed a smaller minimal lumen diameter (MLD) at follow-up (P=0.063). The other two genotypes of AGT and AT1R did not affect restenosis after PCI. According to quinapril treatment, the AGT T homozygotes significantly showed a beneficial effect of quinapril on MLD (P=0.013) and late lumen loss (P=0.013). The ACE I homozygotes also exhibited beneficial effects of quinapril on larger MLD (P=0.065). The AT1R genotype did not influence the quinapril effect. In conclusion, the AGT T homozygotes might benefit from effects of quinapril on preventing restenosis after PCI.

Topics: Angioplasty, Balloon, Coronary; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Coronary Disease; Coronary Restenosis; Female; Gene Frequency; Genotype; Humans; Isoquinolines; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Quinapril; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Tetrahydroisoquinolines

Topics: Angiotensinogen; Case-Control Studies; China; Coronary Disease; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Non-alcoholic Fatty Liver Disease; Polymorphism, Single Nucleotide; Risk Factors

Numerous association studies have been involved in studying the angiotensinogen (AGT) variants, AGT plasma levels and relations to cardiovascular diseases, such as hypertension, myocardial infarction, coronary heart disease. To investigate a role of AGT G(-6)A and M235T genetic variants for chronic heart failure (CHF) and advanced atherosclerosis (AA), a total of 240 patients with CHF and 200 patients with AA of the Czech origin were evaluated for the study. The study shows the role of polymorphism AGT G(-6)A in genetic background among advanced atherosclerosis patients and chronic heart failure patients (Pg=0.001). This difference was also observed in comparison of AA patients with subgroup of CHF with dilated cardiomyopathy (Pg=0.02; Pa=0.009), and ischemic heart disease (Pg=0.007). The greatest difference between triple-vessel disease and chronic heart failure groups was observed in frequency of GT haplotype (P<0.001) and GGMT associated genotype (P<0.001). Retrospectively, we found the same trend when the subgroups of CHF were compared to AA group (AA vs. IHD with CHF P<0.001; AA vs. DCM P<0.001). These results suggest AGT genetic variants as a risk factor for chronic heart failure compared to advanced atherosclerosis disease without heart failure, with a strong difference between IHD patients and chronic heart failure patients with ischemic heart disease, especially in haplotypes and associated genotypes.

Topics: Adult; Aged; Aged, 80 and over; Angiotensinogen; Atherosclerosis; Coronary Disease; Female; Gene Frequency; Genotype; Haplotypes; Heart Failure; Humans; Hypertension; Male; Middle Aged; Polymorphism, Genetic

Recent studies have identified genetic markers that may directly influence the risk of the coronary artery disease (CAD), in particular the renin angiotensin system genes. Since there are no existing data for the Tunisian population, we investigated the association between these polymorphisms (angiotensin-converting enzyme [ACE] insertion/deletion [Ins/Del]; the angiotensinogen T174M and M235T; and the angiotensin II type 1 receptor A1166C polymorphisms) and CAD in Tunisians. Study subjects comprised 341 cases and 316 age- and sex-matched healthy individuals. Clinical characteristics and other biochemical and environmental risk factors were collected for both. The distribution of the Ins/Del genotypes was significantly different between cases and controls (p = 0.049) with the genotype Ins/Ins identified as a risk, p = 0.02. Similarly, the distributions of the T174M and M235T genotypes were significantly different between cases and controls (p = 0.037 and 0.047, respectively) with 174 M/M and 235 T/T as the risky genotypes (p = 0.001 and 0.026, respectively). However, A1166C genotype frequencies were not significantly different between patients and controls. In conclusion, our results suggest that a significantly higher risk of CAD was associated with the Ins/Del, the M235T, and T174M polymorphisms; other environmental variables such as body mass index; and biochemical variables such as cholesterol.

Topics: Adult; Aged; Angiotensinogen; Base Sequence; Case-Control Studies; Coronary Disease; Female; Genetic Predisposition to Disease; Genotype; Haplotypes; Humans; Male; Middle Aged; Molecular Sequence Data; Mutagenesis, Insertional; Mutation, Missense; Peptidyl-Dipeptidase A; Point Mutation; Polymorphism, Genetic; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk; Sequence Deletion; Tunisia

Increased activation of the renin-angiotensin system (RAS) may be important in promoting coronary heart disease (CHD) and renal dysfunction, but limited data are available on associations between angiotensin type 1 receptor (AGT1R) and angiotensinogen (AGT) genotypes in type 2 diabetes.. Study participants were diabetics from the Health Professionals Follow-Up Study (HPFS) and the Nurses' Health Study (NHS). We analyzed single nucleotide polymorphisms (SNPs) associated with cardiovascular pathophysiology (including AGT1R T573C, AGT1R A1166C, and AGT M235T) and presence of renal dysfunction (eGFR<60 ml/min/1.73 m2) or history of CHD.. The AGT1R 1166 C-allele was associated with eGFR<60 ml/min/1.73 m2 (multivariable OR 1.63 [1.01, 2.65]) in the HPFS men (n = 733) and in the combined dataset (n = 1566) (OR 1.42 [1.02, 1.98]). The AGT1R 1166 C-allele was also associated with CHD in men (OR 1.57 [1.10, 2.24]). In NHS women (n = 833), AGT 235T-allele was associated with CHD (OR 1.72 [1.20, 2.47]). Removal of hypertension from the fully adjusted models did not influence results, suggesting that the associations may not be mediated by hypertension. There were significant interactions between sex and AGT1R 1166 C-allele (p = 0.008) and AGT M235T (p = 0.03) in models for CHD. No significant associations were seen between AGT1R T573 C-allele and renal dysfunction or CHD.. Polymorphisms in AGT1R and AGT genes are associated with renal dysfunction and CHD in type 2 diabetes and further support the important role of the RAS in these complications. Sex may modify associations between AGT1R 1166 C-allele and AGT 235T and CHD in type 2 diabetes.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Angiotensinogen; Coronary Disease; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Female; Follow-Up Studies; Gene Frequency; Genotype; Glomerular Filtration Rate; Health Personnel; Humans; Kidney Diseases; Male; Middle Aged; Mutation, Missense; Nurses; Polymorphism, Single Nucleotide; Receptor, Angiotensin, Type 1; Renin-Angiotensin System; Risk; Sex Factors

Recent large association studies have revealed associations between genetic polymorphisms and myocardial infarction and coronary heart disease (CHD). We performed a replication study of 10 polymorphisms and CHD in a population with familial hypercholesterolemia (FH), individuals at extreme risk of CHD.. We genotyped 10 polymorphisms in 2145 FH patients and studied the association between these polymorphisms and CHD in Cox proportional hazards models. We confirmed the associations between four polymorphisms and CHD, the rs1151640 polymorphism in the olfactory receptor family 13 subfamily G member 1 (OR13G1) gene (HR 1.14, 95% CI 1.01-1.28, P = 0.03), the rs11881940 polymorphism in the heterogeneous nuclear ribonucleoprotein U-like 1 (HNRPUL1) gene (HR 1.27, 95% CI 1.07-1.51, P = 0.007), the rs3746731 polymorphism in the complement component 1 q subcomponent receptor 1 (CD93) gene (HR 1.26, 95% CI 1.06-1.49, P = 0.01), and the rs10757274 polymorphism near the cyclin-dependent kinase N2A and N2B (CDKN2A and CDKN2B) genes (HR 1.39, 95% CI 1.15-1.69, P < 0.001).. We confirmed previously found associations between four polymorphisms and CHD, but refuted associations for six other polymorphisms in our large FH population. These findings stress the importance of replication before genetic information can be implemented in the prediction of CHD.

Topics: Adult; Angiotensinogen; Cholesterol; Cohort Studies; Coronary Disease; Female; Genes, p16; Genetic Predisposition to Disease; Genotype; Heterogeneous-Nuclear Ribonucleoproteins; Humans; Hyperlipoproteinemia Type II; Male; Membrane Glycoproteins; Middle Aged; Nuclear Proteins; Polymorphism, Genetic; Receptors, Complement; Receptors, Odorant; Risk Factors; Transcription Factors

The renin-angiotensin system (RAS) is thought to play a major role in the pathophysiology of de-novo restenotic lesions and in-stent restenosis after percutaneous coronary intervention (PCI). Heme oxygenase-1 (HO-1), is thought to beneficially influence these processes. We examined the effect of pharmacologic as well as genetic RAS interactions on restenosis in a large population of consecutive patients undergoing PCI, and evaluated possible gene-gene interactions in both systems.. The GENDER project is a multicenter prospective follow-up study, including 3146 patients after successful PCI. Genotyping in these patients was performed for the ACE gene insertion/deletion, the angiotensinogen 235Met/Thr, T174M and A(-6)G, the angiotensin-II type 1 receptor (AT1R) 1166A/C and T810A, the angiotensin-II type 2 receptor (AT2R) 1675G/A and 3123A polymorphisms and the length polymorphism in the HO-1 promoter region.. A total of 3104 patients were followed for 10 months. In 2975 patients at least one of the nine genotypes could be determined. The AT1R 1166 CC genotype showed a significant association with TVR; the other polymorphisms did not. RAS-inhibitory drugs were not associated with the incidence of TVR, nor did they interact with any of the investigated polymorphisms. Patients with the ACE I/I polymorphism showed a trend towards a better outcome if they had a short number of repeats in the HO-1 promoter. This relationship was inversely present in carriers of the ACE D/D polymorphism.. We could only establish a role for the AT1R 1166A/C polymorphism in restenosis after PCI. However, significant gene-gene interaction was suggested for the ACE gene and the HO-1 promotor. The RAS and HO-1 relation in restenosis merits further investigation.

Topics: Alleles; Angioplasty, Balloon, Coronary; Angiotensinogen; Coronary Disease; Coronary Restenosis; Follow-Up Studies; Heme Oxygenase-1; Humans; Multicenter Studies as Topic; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Promoter Regions, Genetic; Prospective Studies; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Time Factors; Treatment Outcome

The frequencies of angiotensin-converting enzyme gene insertion/deletion, angiotensinogen-M253T, and angiotensin II type 1 receptor-A1166C polymorphisms were analyzed in 105 patients undergoing coronary artery bypass grafting (group 1) and a control group of 105 non-cardiac patients (group 2). Blood samples were obtained for biochemical analyses and DNA extraction. Genotyping was performed by polymerase-chain-reaction-based restriction analysis. According to the angiotensin-converting enzyme gene insertion/deletion polymorphism, 36.3% of patients in group 1 and 30.7% in group 2 were homozygous for the DD allele. This difference was not statistically significant. Angiotensin II type 1 receptor-A1166C genotype polymorphism was also not significantly different between the groups. The results showed the angiotensinogen-M235T polymorphism to be heterogenous. The MM homozygote frequency was significantly higher in controls (72.3%), whereas 80% of the TT homozygote frequency was in the surgical group ( p = 0.001). These results show that although there were no significant differences in angiotensin-converting enzyme gene insertion/deletion and angiotensin II type 1 receptor-A1166C genotype polymorphisms between the groups, angiotensinogen-M235T polymorphism of TT homozygote frequency was significantly associated with patients undergoing coronary artery bypass surgery.

Topics: Aged; Angiotensinogen; Coronary Artery Bypass; Coronary Disease; DNA Transposable Elements; Female; Gene Deletion; Gene Frequency; Humans; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Renin-Angiotensin System

Experimental and clinical studies demonstrated that the renin-angiotensin system (RAS) affects the pathogenesis of atherosclerosis and prognosis of coronary heart disease (CHD). The aim of this study was to investigate the genotype distribution and the allele frequencies of three RAS genes polymorphisms and their effects on premature CHD in a Turkish population.. One-hundred and fifteen Turkish patients with premature CHD and 128 controls were included into the study. Angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) receptor and angiotensinogen (AGT) gene polymorphisms were analysed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP).. The patients group showed an increased frequency of the ACE D allele compared with controls (65% vs. 35%, p = 0.0001). There was a significant association between the DD genotype and premature CHD (ACE DD vs. ID and II; odds ratio [OR] = 2.82 [CI 95% 1.33 2.91, p = 0.002]). Also, we observed increased premature CHD risk associated with higher frequencies of the AGT MM genotype in patients when compared with controls (AGT MM vs. TT and MT, OR = 1.92 [CI 95% 1.11-3.33, p = 0.018]). We found a significant association between AT1-receptor AA genotype and decreased risk of premature CHD (AT1R AA vs. AC and CC, OR = 0.57[CI 95% 0.34-0.95, p = 0.03]).. We demonstrated that increased premature CHD risk is associated with higher frequencies of the ACE DD and AGT MM genotypes. These findings indicate a synergistic contribution of ACE DD and AGT MM polymorphisms to the development of premature CHD. Also, our results suggest that family history, smoking, diabetes, hypertension, obesity and ACE DD genotype were independent risk factors for premature CHD.

Topics: Adult; Angiotensinogen; Case-Control Studies; Coronary Disease; Female; Gene Frequency; Genetic Predisposition to Disease; Genotype; Humans; Male; Middle Aged; Odds Ratio; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Receptor, Angiotensin, Type 1; Time Factors; Turkey

Topics: Aldosterone; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Animals; Coronary Disease; Cytochrome P-450 CYP11B2; Drug Therapy, Combination; Endothelium, Vascular; Fibroblasts; Humans; Lipoproteins, LDL; Mice; Mice, Knockout; Mice, Transgenic; Mineralocorticoid Receptor Antagonists; Muscle, Smooth, Vascular; Myocytes, Cardiac; Nitric Oxide; Rats; Receptor, Angiotensin, Type 1; Receptors, LDL; Receptors, Mineralocorticoid; Receptors, Oxidized LDL; Recombinant Fusion Proteins; Renin; Scavenger Receptors, Class E; Signal Transduction

Topics: Adult; Angiotensinogen; Arteriosclerosis; Blood Coagulation; Cardiovascular Diseases; Coronary Angiography; Coronary Disease; Endothelium, Vascular; Genotype; Heat-Shock Proteins; Hemodynamics; Humans; Hypertension; Male; Myocardial Infarction; Nitric Oxide; Platelet Aggregation; Risk Factors; Vasodilation

Gene encoding components of the renin angiotensin system (RAS) have been implicated with the increased risk of cardiovascular disease (CVD). Two variants of the angiotensinogen (AGT) gene, M235T and T174M, have been shown to be associated with increased risk of hypertension. In the present study, we examined the association of these two polymorphisms and their synergistic interaction with the angiotensin I-converting enzyme (ACE) deletion homozygote genotype (D/D) on subjects with coronary heart disease (CHD) and hypertension. We studied 131 healthy individuals, 141 angiographically verified CHD patients, and 159 hypertensive subjects. The identification of the ACE and AGT gene polymorphisms was carried out using a PCR-based restriction endonuclease digestion method. There was no significant difference in the distribution of the M235T and T174M variants between the two test groups and the control group. Association was also not seen when analysis was carried out in patients when subgrouped according to the extent of the severity of the disease. In addition, the risk was not restricted to subjects carrying the D allele of the ACE gene and T235T of AGT. M235T and T174M variants do not contribute to the increased risk of CHD or hypertension in the Indian population.

Topics: Adult; Angiotensinogen; Apolipoproteins B; Blotting, Southern; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Data Interpretation, Statistical; DNA; fas Receptor; Female; Gene Frequency; Genotype; Humans; Hypertension; India; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Triglycerides

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).. 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.. 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.. 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.. 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.

Topics: Adult; Aged; Angiotensinogen; Coronary Disease; Gene Frequency; Genotype; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptors, Angiotensin; Renin-Angiotensin System; Risk Assessment; Risk Factors

We examined the relationship between the angiotensinogen (AGT) gene M235T polymorphism, the variant promoter of the AGT gene A(-6)G and the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and coronary heart disease (CHD) in native Gran Canaria Island habitants, who have the highest rates of CHD in Spain.. Some studies subject that the ACE (I/D) polymorphism could be associated with CHD, while AGT (M235T) has been related to essential hypertension.. We studied 304 subjects with angiographic evidence of coronary artery disease and a clinical diagnosis of myocardial infarction or unstable angina and 315 age- and gender-matched controls. Blood was drawn and DNA extracted. Angiotensin-converting enzyme (I/D) gene polymorphism was analyzed by polymerase chain reaction (PCR) and AGT gene polymorphisms by restriction fragment length polymorphism-PCR and mutagenically-separated PCR.. The ACE (I/D) polymorphism showed no association with CHD, whereas the frequency distribution of AGT (M235T) genotypes among patients and controls (235T: 29.1% and 19.0%; M235T: 48.5% and 50.2%; M235: 22.4% and 30.8%, respectively) was statistically different (p = 0.005) and not related to the presence of essential hypertension. Similar results were observed with the AGT A(-6)G polymorphism. In multiple logistic regression analysis, CHD odds ratio associated with 235T and M235 homozygotes were 1.7 (1.1 to 2.6) and 0.54 (0.36 to 0.82), respectively.. This study shows that genetic variation of the AGT (M235T), but not the ACE (I/D), genotypes contributes to the presence of CHD independently of blood pressure profile in a subset of the Spanish population with a high prevalence of cardiovascular disease.

Topics: Adult; Aged; Angina, Unstable; Angiotensinogen; Case-Control Studies; Coronary Disease; Female; Gene Deletion; Gene Frequency; Genetic Markers; Genetic Variation; Genotype; Homozygote; Humans; Logistic Models; Male; Middle Aged; Mutagenesis, Insertional; Myocardial Infarction; Odds Ratio; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Prevalence; Promoter Regions, Genetic; Radiography; Renin-Angiotensin System; Risk Factors; Spain

Molecular variants of the angiotensinogen (AGT) and the angiotensin II type 1 receptor (ATR) genes have been associated with the risk of coronary artery disease (CAD) and myocardial infarction (MI), but data so far available are conflicting. The primary object of the paper is to verify this possible association by a rigorous, angiographically controlled study in a large sample of patients with or without multi-vessel CAD.. We designed a large case-control study in Italian patients candidates for coronary artery bypass grafting, with angiographically documented multi-vessel CAD, compared to subjects with angiographically documented normal coronary arteries.. AGT M235T and ATR A1166C gene polymorphisms were analysed in 699 subjects; 454 patients were candidates for coronary artery bypass grafting, having angiographically documented (mainly multi-vessel) CAD. An appropriate documentation of previous MI was obtained from 404/454 (89%, 247 with and 157 without MI). Subjects (n = 245) with angiographically documented normal coronary arteries, were included as control group (CAD-free group). CAD patients had a substantial burden of conventional risk factors as compared with controls free of coronary atherosclerosis. Age, gender, smoking habit and number of stenosed vessels were the only differences between patients with or without previous myocardial infarction, who were similarly exposed to the other conventional risk factors (including hypertension). AGT M235T and ATR A1166C allele and genotype frequencies were similar between CAD and CAD-free patients. In the CAD group, AGT 235T allele was found more frequently in subjects with a previous myocardial infarction (0.494 versus 0.414; P < or = 0.05). By logistic regression, homozygosity for AGT 235T variant appeared to confer 1.9-fold increased risk for MI in both the univariate and the multivariate (adjusted for age, gender, smoking habit and number of stenosed vessels) model.. AGT 235 T homozygous patients with multivessel CAD have an increased risk of myocardial infarction as compared with subjects with clinically similar phenotype but different genotype.

Topics: Aged; Angiotensinogen; Coronary Disease; Female; Genetic Predisposition to Disease; Genetic Variation; Genotype; Homozygote; Humans; Male; Middle Aged; Myocardial Infarction; Phenotype

The thymidine to cytosine transition at position 704 in exon 2 of the angiotensinogen gene leads to the amino acid substitution of threonine for methionine (T235 variant) and is responsible for elevated plasma levels of angiotensinogen. To examine the influence of T235 on the risk of coronary artery disease (CAD) we genotyped 184 CAD patients, 77 controls in whom CAD was excluded angiographically, and 155 healthy controls without signs of CAD by polymerase chain amplification and restriction enzyme digestion. Allele frequencies for A (wildtype) and a (mutant allele) in the total study population were 0.538 and 0.462, 0.536 and 0.464 in the healthy controls, and 0.481 and 0.519 in patients with excluded CAD, respectively. The allele frequencies and the genotype distribution in these groups did not show a significant difference. In conclusion, we did not observe an association between the T235 variant of the angiotensinogen gene and the risk of CAD.

Topics: Amino Acid Substitution; Angiotensinogen; Coronary Angiography; Coronary Disease; DNA; Electrophoresis, Agar Gel; Female; Genotype; Germany; Humans; Male; Middle Aged; Polymorphism, Genetic; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors

Polymorphisms within renin angiotensin system genes have been investigated as risk factors for coronary artery disease in different populations with contradicting results. The aim of this study was to investigate the genotype distribution and the allele frequencies of ACE, AT1R and AGT gene polymorphisms as coronary artery disease factors and their synergistic effects on coronary risk in an Italian population. METHODS AND RESULTDS: In this study ACE, AT1R and AGT gene polymorphisms were investigated in 205 consecutive coronary artery disease patients and in 209 controls. These polymorphisms were analysed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). The ACE D and AGT 235T allele, but not AT1R C allele, frequency was statistically significant in patients. An association between coronary artery disease and ACE DD, AT1R CC and AGT TT genotype, was found by univariate analysis (OR 2.06 P=0.0007, OR 2.49 P=0.009, OR 1.87 P=0. 019, respectively). At multivariate analysis ACE DD and AT1R CC genotype (OR 1.81 P=0.011, OR 2.61 P=0.011, respectively) remained associated with coronary heart disease. Subjects carrying the ACE DD genotype and AT1R C allele showed a stronger association with myocardial infarction (OR=4.02, P<0.0001).. Our report indicates the increased risk of coronary artery disease in the presence of ACE DD and AT1R CC genotypes independent of other risk factors, in Italian patients. The present study stresses the relevance of screening for genetic risk factors.

Topics: Alleles; Angiotensinogen; Case-Control Studies; Coronary Disease; Female; Gene Frequency; Genotype; Humans; Italy; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Receptors, Angiotensin; Risk Factors; White People

Patients with insulin-dependent diabetes mellitus (IDDM) have a high risk of developing diabetic nephropathy, retinopathy and cardiovascular diseases. The contribution of gene polymorphisms of the renin angiotensin system to these complications is controversial and may differ among populations.. In 257 Dutch IDDM patients (188 with urinary albumin excretion (UAE) <30 mg/24 h), logistic regression analysis was used to study the relationships among, on the one hand, the insertion/deletion gene polymorphism of the angiotensin-converting enzyme gene (ACE-ID), the M235T gene polymorphism of the angiotensinogen gene (AGT-M235T), and the A1166C gene polymorphism of the angiotensin type 1 receptor gene (AT1-A1166C), and, on the other hand, UAE, retinopathy, hypertension, and coronary heart disease.. The T-allele of the AGT-M235T polymorphism was associated with an increased risk of an elevated UAE (odds ratio (OR) 3.03; 95% confidence interval (CI) 1.06-8.61), but only when interaction with the D-allele of the ACE-ID polymorphism was considered. A previously described positive interaction between the T-allele of the AGT-M235T polymorphism and the D-allele of the ACE-ID polymorphism could not be confirmed. The T-allele was also associated with an increased risk of retinopathy (OR 3.89, 95% CI 1.79-8.47). The CC-genotype of the AT1-A1166C polymorphism was associated with hypertension (OR 3.58; 95% CI 1. 23-10.37).. In a Dutch IDDM population, including 69 patients with (incipient) diabetic nephropathy, the T-allele of the AGT-M235T polymorphism is associated with an elevated UAE and diabetic retinopathy and the CC-genotype of the AT1-A1166C polymorphism is associated with hypertension. A previously described interaction between the AGT-M235T and the ACE-ID polymorphisms could not be confirmed. Since the number of nephropathic patients in this study is small, these conclusions must be interpreted with caution.

Topics: Adult; Aged; Albuminuria; Angiotensinogen; Coronary Disease; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Retinopathy; DNA Transposable Elements; Gene Deletion; Humans; Hypertension; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Renin-Angiotensin System

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.

Topics: Alleles; Angioplasty, Balloon, Coronary; Angiotensinogen; Coronary Disease; Female; Genotype; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Predictive Value of Tests; Receptors, Angiotensin; Recurrence; Risk Factors

The role of renin-angiotensin system polymorphisms as risk factors for coronary heart disease (CHD) is controversial. This study investigated their role in patients with heterozygous familial hypercholesterolemia (FH). Polymorphism frequencies for angiotensin-I-converting enzyme insertion/deletion (ACE I/D), angiotensinogen M235T, and angiotensin-II type I receptor (AG2R) A1166C were determined in 112 patients with FH and 72 patients with polygenic hypercholesterolemia, of whom 26.7% and 41.6%, respectively, had established CHD. None of the polymorphisms were associated with risk of CHD in patients with polygenic hypercholesterolemia in this study. Logistic regression analysis of risk factors for CHD in patients with FH identified male sex (odds ratio [OR]=3.03; 95% CI, 3.07 to 3.72; P=0.05), smoking (OR=2.91; 95% CI, 2.16 to 4.24; P=0.05), diastolic blood pressure (OR=3.70; 95% CI, 3.43 to 3.97; P=0.02), plasma glucose (OR=3.31; 95% CI, 3. 10 to 3.52; P=0.04), and the AG2R A1166C polymorphism as risk factors. The OR for the AG2R A1166C polymorphism was 2.26 (95% CI, 1.26 to 3.72; P=0.06) and increased to 3.10 (95% CI, 1.20 to 7.52; P=0.04) after adjustment for other risk factors. The AG2R A1166C polymorphism may interact with severe hypercholesterolemia and other risk factors to increase risk of CHD in FH patients.

Topics: Adult; Aged; Angiotensinogen; Blood Pressure; Cholesterol; Coronary Disease; Female; Genotype; Humans; Hyperlipidemias; Hyperlipoproteinemia Type I; Logistic Models; Male; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Angiotensin; Regression Analysis; Renin-Angiotensin System; Risk Factors; Smoking; Triglycerides

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).. 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).. Our observations allow the assumption that the p22 phox A640G gene polymorphism is independently associated with the presence and extent of coronary artery disease.

Topics: Adenine; Angiotensinogen; Apolipoprotein A-I; Apolipoproteins B; Aryldialkylphosphatase; Coronary Angiography; Coronary Disease; Cytosine; Esterases; Gene Deletion; Genetic Variation; Guanine; Humans; Lipoprotein(a); Male; Membrane Transport Proteins; Middle Aged; NADPH Dehydrogenase; NADPH Oxidases; Phosphoproteins; Polymorphism, Genetic; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Risk Factors; Thymidine

Variants of the angiotensinogen gene may increase the risk of having arterial hypertension and coronary heart disease (CHD), but their effect on insulin resistance remains unknown.. We determined M235 and T174 allele status and fasting plasma glucose, insulin, and lipids values in nondiabetic men with CHD documented on angiography (n = 102) and in a control group (n = 145). Plasma glucose and insulin responses to 75 gm oral glucose tolerant test and insulin resistance as measured by an insulin suppression test were also carried out in 46 (45%) patients with CHD and in 73 (50%) members of a control group.. We found no association between M235T status and blood pressure, fasting plasma glucose, insulin, most of the lipids values, and insulin resistance in patients with CHD and normal subjects. Nevertheless, compared with individuals with homozygotes T174, subjects with heterozygotes T174M were associated with greater glucose and insulin response to the oral glucose tolerance test and insulin resistance indicated by higher steady state plasma glucose concentrations in patients with CHD (14.7+/-0.9 vs 11.3+/-0.7 mmol/L, p < 0.04). Similar findings were found in the control group, with higher steady-state plasma glucose values in individuals with heterozygotes T174M than in those with homozygotes T174 (10.1+/-1.4 vs 7.7+/-0.4 mmol/L, p < 0.05).. We suggest that the angiotensinogen T174M allele might be associated with insulin resistance in nondiabetic men with and without CHD.

Topics: Alleles; Angiotensinogen; Blood Glucose; Coronary Angiography; Coronary Disease; DNA; Electrocardiography; Genotype; Glucose Tolerance Test; Humans; Insulin; Insulin Resistance; Male; Middle Aged; Polymerase Chain Reaction; Polymorphism, Genetic; Risk Factors

The relationship between coronary artery disease (CAD) and polymorphisms of genes encoding angiotensinogen (AGT) and angiotensin converting enzyme (ACE) was analyzed in Japanese subjects. One hundred and four patients with CAD and 170 healthy subjects were enrolled in the study. CAD was defined as having a luminal diameter stenosis > or =50% in at least one of three major coronary arteries by coronary angiography. The genotypes (determined by polymerase chain reaction) of AGT gene codon 174 were not significantly associated with CAD in the total study population. However, the frequency of T/T homozygotes of AGT codon 174 was significantly higher in CAD patients compared to controls in each of three subgroups: 1) body mass index (BMI) below the median value of 24.1 kg/m2; 2) not more than two CAD risk factors out of five (hypercholesterolemia, hypertension, diabetes mellitus, smoking, and family history of CAD); and 3) the ACE I/I genotype. The M/M genotype of AGT codon 235 was negatively associated, and the ACE D/D genotype was positively associated, with CAD in the total study population. Our results indicate that the T/T genotype of AGT codon 174 may be a risk factor for CAD in Japanese individuals with low BMI, lesser CAD risk factors, or ACE I/I genotype.

Topics: Aged; Angiotensinogen; Coronary Disease; Female; Gene Frequency; Genotype; Humans; Japan; Middle Aged; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors

Genetic polymorphisms of the renin-angiotensin system (RAS) have been associated with coronary artery disease (CAD) but no relation between these polymorphisms and coronary atherosclerosis has yet been systematically evaluated. The CORGENE study is a cross-sectional study involving 463 Caucasians who underwent standardized coronary angiography for established or suspected CAD [156 patients with a previous myocardial infarction (MI), 307 without MI]. Four angiographic scores assessing the extent and severity of the coronary lesions were obtained from a double visual analysis of each angiogram, arbitration being achieved by a quantitative measurement. Three different genotypes were analyzed: the angiotensin I-converting enzyme insertion/deletion (ACE I/D) polymorphism, the Met to Thr change at position 235 of the angiotensinogen gene (AGT M235T) and the A to C transition at position 1166 of the angiotensin II type-1 receptor gene (AT1R A1166C). No significant association was observed between these polymorphisms and the clinical characteristics of MI and non-MI subjects. While most classical risk factors were positively correlated with the angiographic scores, no significant relationship could be established with the three genotypes (r ranging from -0.08 to 0.05). Only one significant correlation was observed: between the presence of the AGT 235T allele and the extent of the coronary lesions (r = -0.19, P = 0.04) in patients with low-risk status. These overall results are not in favor of a role of these RAS genetic polymorphisms in the development of coronary atherosclerosis.

Topics: Angiotensinogen; Coronary Angiography; Coronary Disease; Cross-Sectional Studies; Diabetes Mellitus; DNA Transposable Elements; Family; Female; France; Gene Frequency; Genotype; Humans; Male; Middle Aged; Myocardial Infarction; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Receptors, Angiotensin; Renin-Angiotensin System; Risk Assessment; Sequence Deletion; White People

Angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) are major components of the renin-angiotensin systems. An association between myocardial infarction (MI) and the ACE DD genotype of the insertion/deletion (ID) polymorphism in intron 16 of the ACE gene has been reported. However, other similarly designed studies have not found such an association. Angiotensin II, the product of AGT, has a direct effect on vascular tone; and a variant in the AGT gene has been found to be associated with MI in the Japanese. This case-control study was initiated to investigate whether the ACEI/D and AGT M235T polymorphisms are associated with an increased risk for coronary heart disease (CHD) and MI. Our study groups were composed of participants in the National Heart Lung Blood Institute (NHLBI) Family Heart Study (FHS) selected from three population-based studies: two Atherosclerosis Risk in Communities (ARIC) centers (Forsyth County, NC, and Minneapolis, MN), and the Framingham Heart Study. In multivariate analysis within ARIC Caucasians, a significant positive association was found between CHD (controls = 230, cases = 232) and the AGT TT genotype (P = 0.022; OR = 1.84, 1.09-3.10 95% CI). When we restricted the analysis to a low-risk group for CHD (controls = 70, cases = 35) an interaction between the ACE DD and AGT TT genotypes was significant (P = 0.025; OR = 5.02 1.22-20.6 95% CI). After further subsetting low-risk cases to those with a definite MI (controls = 74, cases = 16), we found that the associations with the ACE DD genotype was also significant (P = 0.013, OR = 3.94, 1.28-12.2 95% CI). Comparable tests in the Framingham sample failed to support an association of these markers with CHD. In conclusion, within selected groups the ACE D and AGT 235T alleles are statistically associated with CHD and MI, and there is a synergistic interaction between the two alleles. These results and those from previous studies together suggest that the association of these two loci is neither strong nor consistent and involves a complex interaction among risk factors and genotypes.

Topics: Angiotensinogen; Black People; Body Mass Index; Case-Control Studies; Coronary Disease; Female; Gene Deletion; Genotype; Humans; Logistic Models; Male; Massachusetts; Minnesota; Myocardial Infarction; North Carolina; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors; White People

In studies conducted in several different populations, the M235T substitution in the angiotensinogen (AGT) locus has been associated with hypertension.. A case-control study was initiated in an attempt to replicate this finding. Persons with hypertension, age- and sex-matched normotensive controls, and randomly sampled individuals were probands from the Family Heart Study of the National Heart, Lung, and Blood Institute. Subjects were recruited from the Atherosclerosis Risk in Communities study (ARIC) in North Carolina and Minneapolis, MN, and from the Framingham Heart Study in Massachusetts. Genotypes were determined for the M235T substitution in the AGT locus and for the insertion/deletion polymorphism in the angiotensin-converting enzyme (ACE) locus. Simple association tests as well as logistic regression analyses were performed.. The association of AGT-T235 with hypertension was replicated in the Framingham sample (odds ratio, 1.60; 95% confidence interval, 1.11-2.30), but not in the ARIC white or black subjects. However, logistic regression analysis suggested a significant association of AGT with hypertension in both the ARIC white and Framingham samples when the effects of body mass index, triglycerides, and the presence of significant coronary heart disease were controlled. These analyses further suggested that, in the ARIC data, the relationship with the AGT locus is stronger in women than men and that there may be interaction (epistasis) between homozygotes for T235 and ACE-DD in the Framingham data. While the small sample size precluded logistic regression analysis, the frequency of the T235 allele in the black random sample was much higher than in the comparable white sample.. These results are compatible with the presence of a genetic risk factor for hypertension in or near the angiotensinogen locus.

Topics: Angiotensinogen; Black People; Body Mass Index; Case-Control Studies; Coronary Disease; Female; Genotype; Humans; Hypertension; Logistic Models; Male; Massachusetts; Middle Aged; Minnesota; North Carolina; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors; Sex Factors; Triglycerides; White People

The Keewatin Inuit of the Northwest Territories of Canada have a very low age-adjusted mortality rate from coronary heart disease. We hypothesized that this apparent protection from disease has a genetic basis. We determined the prevalence of the disease-associated alleles of five candidate genes for atherosclerosis-related phenotypes. Surprisingly, four of the five alleles studied, namely AGT T235, FABP2 T54, PON R192 and APOE E4, were significantly more frequent in a sample of 175 Keewatin Inuit than among a representative control sample of whites living in the region. The high frequencies of these disease-associated alleles suggests either that they have no relationship with disease susceptibility in the Inuit, or that some unmeasured genetic and/or environmental factors mitigate disease susceptibility that is associated with these alleles. This highlights the difficulty in extrapolating findings from one population to another. Also, very modest genotype-phenotype associations were observed between APOE genotype (P = 0.016) and plasma low-density lipoprotein cholesterol concentration and between FABP2 genotype and plasma 2-h postprandial, glucose concentration (P = 0.048). The relationship between APOE alleles and plasma low-density lipoprotein cholesterol was the same as has been previously reported in many study samples. However, the relationship between FABP2 alleles and plasma 2-h postprandial glucose concentrations was the opposite to that reported in other studies. This suggests that differences in environment, such as the type of fatty acid consumed, interacts with functional differences in gene products involved in candidate metabolic pathways to produce phenotypic differences.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Alleles; Angiotensinogen; Apolipoproteins E; Aryldialkylphosphatase; Canada; Carrier Proteins; Coronary Disease; Esterases; Fatty Acid-Binding Protein 7; Fatty Acid-Binding Proteins; Female; Gene Frequency; Genetic Variation; Humans; Inuit; Male; Middle Aged; Myelin P2 Protein; Neoplasm Proteins; Peptidyl-Dipeptidase A; Phenotype; Risk Factors; Tumor Suppressor Proteins

The homozygous deletion allele (DD) of the angiotensin-I converting enzyme (ACE) gene and the T235 homozygote of the angiotensinogen (AGT) gene have been reported to be correlated with an increased prevalence of coronary artery disease (CAD) and myocardial infarction (MI). The importance of the DD genotype and T235 homozygote as genetic risk factors for CAD in Chinese remains uncertain. This study included 426 patients who underwent coronary angiography and 180 healthy subjects without clinical evidence of CAD. Coronary angiography identified 268 patients with CAD (CAD group) and 158 patients without CAD. The healthy subjects and patients without angiographic evidence of CAD constituted the control group. Three polymorphisms were studied: an insertion/deletion (I/D) polymorphism of the ACE gene and the T174 M and M235T polymorphisms of the AGT gene. No association was found between any of the three studied polymorphisms and the risk of CAD or MI in Chinese using univariate or multivariate analysis. In multivariate analysis, the relative risks were 1.20 (95% confidence interval = 0.91-1.61, P = 0.20) for the DD genotype, 1.05 (95% CI = 0.82-1.35, P = 0.69) for the T174 homozygote, and 1.19 (95% CI = 0.91-1.55, P = 0.20) for the T235 homozygote. Similarly, no significant difference was found in the frequencies of the DD genotype and the T174 and T235 homozygotes between the control group, the CAD group, the non-MI group, and the MI group when analyzed according to sex, age, or degree of risk. Our data suggest that neither the DD genotype of the ACE I/D polymorphism nor the T174 and T235 homozygotes of the AGT gene confer significant risk for CAD or MI in Chinese.

Topics: Angiotensinogen; China; Coronary Disease; Environmental Medicine; Female; Gene Frequency; Genotype; Humans; Logistic Models; Male; Middle Aged; Multivariate Analysis; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors; Taiwan

The renin-angiotensin system is important in cardiovascular remodeling. Although a variant of the angiotensinogen gene is associated with an increased generation of angiotensinogen, it is unclear how this genetic variant might influence the activity of the renin-angiotensin system and thereby contribute to the predisposition to coronary artery disease (CAD). The relation between genetic polymorphisms in the gene-encoding angiotensinogen and the risk of CAD in middle-aged Japanese men was investigated. Two polymorphisms in exon 2 of the angiotensinogen gene, M235T and T174M, were analyzed in 327 patients with CAD and 352 matched control subjects. The genotype distribution of both polymorphisms did not differ between patients with CAD and control subjects. No combination of genotypes of the two polymorphisms was associated with CAD. Results indicate that the M235T and T174M variants of the angiotensinogen gene are not associated with CAD in Japanese men.

Topics: Angiotensinogen; Case-Control Studies; Coronary Disease; Gene Frequency; Genotype; Humans; Japan; Logistic Models; Male; Middle Aged; Risk Factors

We previously found an association between blood pressure and genetic variation of angiotensinogen in Canadian Hutterites. We hypothesized that variation in other candidate genes would also be associated with variation in blood pressure. We included genotypes of 12 candidate genes, along with clinical features and biochemical variables as covariates in an association analysis. We found that sex and body mass were significantly associated with variation in both systolic and diastolic blood pressures. We found that genotypes of APOB codon 4154 and AGT codon 174 were significantly associated with variation in systolic blood pressure. We found that genotypes of APOB codon 4154, AGT codon 174, and F7 codon 353 were significantly associated with variation in diastolic blood pressure. We found a significant association between age and variation in systolic but not diastolic blood pressure. We found a significant association between plasma apo B concentration and variation in diastolic but not systolic blood pressure. The association of genomic variation with resting blood pressure is consistent with the existence of important structural elements within or proximal to some genes in lipoprotein metabolism, the renin-angiotensin system, and the coagulation cascade. The association between plasma apo B concentration and diastolic blood pressure suggests that these traits may share some determinants.

Topics: Angiotensinogen; Apolipoproteins B; Blood Pressure; Canada; Christianity; Codon; Coronary Disease; Ethnicity; Genetic Markers; Genetic Variation; Genotype; Homozygote; Humans; Lipoproteins; Prevalence; Renin-Angiotensin System; Risk Factors; United States

Recently we found that the deletion (D) allele of the insertion/deletion (I/D) polymorphism of the ACE gene in 404 children was associated with a history of coronary artery disease (CAD) in their grandparents. This led us to explore polymorphisms in other genes of the renin-angiotensin system in this same population.. We determined the genotypes for three microsatellite markers located near or in the angiotensinogen, angiotensin II (type-1) receptor, and renin genes in the children and related the allele frequencies to grandparental CAD. We found a significant association between the angiotensinogen marker in children and grandparental CAD (chi2 = 42.2, P = .00001) with these children having an excess of the 125-bp and 129-bp alleles (odds ratio, 2.5; 95% confidence interval, 1.7 to 3.7). Greatest grandparental risk was when their grandchildren had the 125-bp/125-bp, 129-bp/129-bp, or 125-bp/129-bp genotypes (odds ratio, 7.75; 95% confidence interval, 2.2 to 27). There was no association between the microsatellites at either the angiotensin II (type-1) receptor (P = .8) or renin (P = .2) genes in children and grandparental CAD and none between the angiotensinogen and ACE polymorphisms in relation to CAD family history.. This study identifies a significant association between an angiotensinogen marker in children and grandparental CAD. There was no association between the microsatellites at either the angiotensin II (type-1) receptor or renin genes and CAD in this population. We conclude that the angiotensinogen polymorphism as well as the ACE polymorphism may explain a part of the risk related to a family history of CAD.

Topics: Adolescent; Alleles; Angiotensinogen; Base Sequence; Child; Child, Preschool; Coronary Disease; Female; Gene Frequency; Genotype; Humans; Male; Medical Records; Microsatellite Repeats; Molecular Probes; Molecular Sequence Data; Receptors, Angiotensin; Renin

Topics: Angiotensinogen; Case-Control Studies; Coronary Disease; Gene Frequency; Genetic Markers; Genotype; Humans; Peptidyl-Dipeptidase A; Polymorphism, Genetic

Topics: Alleles; Angiotensinogen; Coronary Disease; Female; Gene Frequency; Genotype; Humans; Japan; Male; Middle Aged; Oligonucleotide Probes; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors

Topics: Alleles; Angiotensinogen; Coronary Disease; Female; Humans; Male; Middle Aged; Peptidyl-Dipeptidase A; Risk Factors

Several genes, including some encoding components of the renin angiotensin system, are associated with the risk of cardiovascular diseases. There have been reports linking a homozygous deletion allele of the angiotensin converting enzyme (ACE) gene (DD) with an increased risk of myocardial infarction, and some variants of the angiotensinogen gene with an increased risk of hypertension. In a case-control study of a caucasian population from New Zealand, we examined the associations with coronary heart disease (CHD) of ACE DD and of a mis-sense mutation with methionine to threonine aminoacid substitution at codon 235 in the angiotensinogen gene (T235). We studied 422 patients (mean age 62 years, 81% male) with documented CHD (50% with myocardial infarction) and 406 controls without known CHD (frequency-matched to cases by age and sex). Risk factors for CHD were assessed by standard questionnaire, physical examination, and blood tests. Genomic DNA from leucocytes was analysed for various ACE and angiotensinogen alleles. Angiotensinogen T235 homozygotes were at significantly increased risk of CHD generally (odds ratio 1.7, 2 p = 0.008) and of myocardial infarction specifically (1.8, 2 p = 0.009). Adjustment for several risk factors increased the estimate of CHD risk associated with this allele to 2.6 (2 p < 0.001) and the estimate for myocardial infarction risk to 3.4 (2 p < 0.001). By contrast, there was no evidence of a significant increase in the risk of CHD or myocardial infarction among individuals with ACE DD. We conclude that the T235 polymorphism of the angiotensinogen gene is an independent risk factor, which carries an approximately two-fold increased risk of CHD. In this study, however, ACE DD was not associated with any detectable increase in CHD risk.

Topics: Alleles; Angiotensinogen; Base Sequence; Coronary Disease; DNA; DNA Primers; Female; Genetic Variation; Humans; Male; Middle Aged; Molecular Sequence Data; Mutation; Peptidyl-Dipeptidase A; Polymorphism, Genetic; Risk Factors

A moderate elevation of the daily excretion of free noradrenaline and adrenalin is observed in chronic circulatory insufficiency, beginning with Stage IIA. The catecholamines metabolism is elevated, as shown by the daily excretion of normethanpherine and methanpherine and of vanillyl-mandelic acid. The activity of renin and angiotensinases was growing along with the progressing cardiac insufficiency. The blood level of angiotensinogen was decreasing, especially in patients with Stage IIB and III of decompensation. The daily excretion of aldosterone was growing along with the development of cardiac insufficiency. The functional state of the glucocorticoid function of the adrenal cortex was of a phased nature in cases of circulatory insufficiency. The study of the functional state of the epiphysis was conducted by way of determining the blood level of melatonine and of its daily excretion. In Stages I and IIA the level of this hormone was clearly elevated, in Stages IIB and III -- decreased as compared with the initial and normal levels. The plasma level of the antidiuretic hormone was distinctly growing, beginning with Stage IIB, reaching its maximal values in Stage III.

Topics: 17-Ketosteroids; Adult; Aged; Aldosterone; Angiotensinogen; Coronary Disease; Cortisone; Endopeptidases; Epinephrine; Female; Heart Failure; Humans; Hydrocortisone; Hypertension; Male; Melatonin; Metanephrine; Middle Aged; Norepinephrine; Normetanephrine; Renin; Tetrahydrocortisol; Tetrahydrocortisone; Vanilmandelic Acid