Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085580 (essential hypertension)
 14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Angiotensinogen exhibits genetic linkage to and association with essential hypertension and preeclampsia, a common hypertensive disorder of pregnancy; however, the polymorphisms detected thus far provide no functional clues. In a preeclamptic patient, we have identified a mutation leading to the replacement of leucine by phenylalanine at position 10 of mature angiotensinogen (L10F), the site of renin cleavage. Kinetic analyses of the enzymes of the renin-angiotensin system, using either model peptides or full-length substrates, show that this mutation significantly alters the reactions with both renin and angiotensin-converting enzyme. For the renin reaction on a full-length substrate, this substitution leads to a 10-fold decrease in Km (from 1.1 to 0.09 microM) and a 5-fold decrease in kcat (from 1.0 to 0.22 s-1); as a result, catalytic efficiency (kcat/Km) is increased by a factor of 2 (1.1 versus 2.4 microM-1 s-1). In the reaction of angiotensin-converting enzyme on angiotensin decapeptides, the substitution has no effect on Km (38.0 versus 30.0 microM), but increases kcat and catalytic efficiency > 2-fold (kcat = 15.0 versus 37.0 s-1; kcat/Km = 0.41 versus 1.23). The renin-angiotensin system, challenged by the profound physiological adaptations of pregnancy, is perturbed in preeclampsia; consequently, the L10F mutation may promote this condition in carrier subjects.
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PMID:A mutation of angiotensinogen in a patient with preeclampsia leads to altered kinetics of the renin-angiotensin system. 774 80

The factors that initiate chronic renal failure in patients with hypertension, diabetes mellitus, and chronic glomerular disease are largely unknown. The likely genetic contribution to ESRD, particularly in African Americans, suggests that linkage analysis may be useful to evaluate the role of candidate genes in the pathogenesis of chronic renal failure. The renin-angiotensin-aldosterone (RAA) axis has been intensively evaluated for its contribution to cardiovascular disease and nephropathy. This study tested for linkage between candidate genes in the RAA axis and chronic renal failure, using 85 African-American sibling pairs (from 65 families) concordant for ESRD. Angiotensinogen was selected because of the putative link between it and mild to moderate essential hypertension and nephrosclerosis; angiotensin-converting enzyme because of its possible contribution to diabetic nephropathy; and renin, the angiotensin II receptor, and kallikrein because of their roles in hypertension and renal perfusion. These candidate loci did not demonstrate linkage to either diabetic or nondiabetic renal disease in this study's collection of sibling pairs. These results suggest that polymorphisms at these RAA axis loci do not make major contributions to the pathogenesis of renal disease in African Americans.
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PMID:Linkage analysis between loci in the renin-angiotensin axis and end-stage renal disease in African Americans. 898 34

The renin-angiotensin system (RAS) is involved in the pathogenesis of essential hypertension. In the present study we examined the genotype frequencies of the insertion/deletion polymorphisms of the ACE gene and the M235T polymorphism of the Angiotensinogen (Agt) gene in patients with essential hypertension in comparison with normotensive subjects. In hypertensive patients functional effects of blood pressure response to ACE inhibition were investigated. A total of 121 patients with essential hypertension (group 1) and 125 normotensive control subjects (group 2) were included in this study. All patients were genotyped by polymerase chain reactions (PCR) for the insertion/deletion (I/D) polymorphism of the ACE gene and the M235T polymorphism of the Agt gene. To analyze possible functional impacts on blood pressure regulation 50 mg of captopril was administered to hypertensive patients. No significant association of essential hypertension with polymorphisms of the Agt and ACE gene was found. The ACE serum levels in patients with the DD-genotype of the ACE I/D polymorphism were higher than in patients with the II-genotype (P < .01). In patients with the ID-genotype the ACE serum levels were in-between. A captopril test was performed in hypertensive patients. The patients were further divided into subgroups according to the diastolic and systolic blood pressure response. Group 1a consisted of patients with a diastolic blood pressure drop of > 5 mm Hg and group 1b with < or =5 mm Hg. Group 1c consisted of patients with a systolic blood pressure drop of > 10 mm Hg and group 1d with < or =10 mm Hg. Twice as many patients with the DD genotype of the ACE gene were found in group 1a compared to group 1b (chi(2) = 5.673; P = .017). No association of systolic blood pressure change to the investigated polymorphisms was found. Our results do not support the hypothesis that the investigated polymorphisms contribute to essential hypertension. Furthermore, no major impact of these polymorphisms on blood pressure response to captopril were detected. We conclude that the investigated genotypes have no influence on blood pressure level and homeostasis.
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PMID:Contribution of angiotensin I converting enzyme gene polymorphism and angiotensinogen gene polymorphism to blood pressure regulation in essential hypertension. 952 45

Angiotensinogen is the glycoprotein precursor of one of the most potent vasoactive hormones, angiotensin-II. Angiotensinogen gene is primarily expressed in the liver, and this gene locus is linked with human essential hypertension. We show here that a mutation in exon-I reduces the basal expression of the human angiotensinogen gene in liver cells. We also show that a nucleotide sequence in exon-I binds to liver-enriched transcription factor HNF-3 and a ubiquitous factor AP4. Our studies also show that transient transfection of an expression vector containing AP4 coding sequence downregulates the expression of reporter constructs containing human angiotensinogen gene promoter. By contrast, co-transfection of an expression vector containing HNF-3beta coding sequence increases the expression of these reporter constructs. The human angiotensinogen gene has a C/A polymorphism located at -20, and we have shown that estrogen receptor-alpha binds to this sequence when nucleoside A is present at this site. We show here that co-transfection of an expression vector containing AP4 coding sequence reduces estrogen-induced promoter activity of reporter constructs containing human angiotensinogen gene promoter (with nucleoside A at -20) attached to the CAT gene. These studies partly explain the molecular mechanisms involved in tissue-specific expression of the human angiotensinogen gene.
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PMID:Exon-I is involved in positive as well as negative regulation of human angiotensinogen gene expression. 993 57

Essential hypertension is a complex disease influenced by different genetic and environmental factors. The renin-angiotensin system (RAS) is implicated in blood pressure regulation. Angiotensinogen (AGT) is the precursor of the biologically active angiotensin II (Ang II). Initial studies on hypertensive siblings and case-control studies indicated the important role of the angiotensinogen gene (AGT) for the predisposition to essential hypertension, preeclampsia and obesity-related hypertension. Recently, different AGT polymorphisms had been identified and analyzed in case-control studies. The aim of present studies is the analysis of potentially functional AGT variants (C-532T, G-6A), which might be responsible for the regulation of gene expression and therefore AGT generation. The A-6 allele is in complete linkage disequilibrium with the T235 allele and is associated with higher AGT expression in vitro. Segregation linkage analysis demonstrated that the C-532T polymorphism influences plasma AGT variability more significantly than the G-6A variant. Since the C-532T polymorphism is located within a AP-2 consensus element, functional promoter analyses are required. The understanding of the molecular basis of RAS in essential hypertension may provide us with new and more specific pharmacological agents and perhaps the ability to individualize antihypertensive treatment.
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PMID:[Role of the angiotensinogen gene for essential hypertension]. 1071 6

Essential Hypertension (EH) is a multifactorial and polygenic syndrome with a high impact in public health. Recently, rare mendelian forms of hypertension such as glucocorticoid-remediable aldosteronism (GRA), apparent mineralocorticoid excess (AME) and Liddle Syndrome caused by single gene mutations have been identified in which the mechanism is an increased sodium retention. Therefore, it is tempting to speculate that the most common forms of EH may be due to diverse highly prevalent molecular variants of susceptibility genes with low penetrance that are involved in arterial blood pressure (ABP) and electrolytic balance. Although a number of candidate genes such as NO synthases, ANP, ion transporters, adducins, LDL receptor, etc. can participate, renin-angiotensin system components are the most extensively studied. Although not associated with EH, the ACE D allele seems to confer a high risk of CHD or LVH. Angiotensinogen 235T and 174M variants are more likely associated with EH and positively correlate with clinical or ambulatory ABP in adolescents or adults. Individuals who carry these angiotensinogen alleles would be at 1.4 higher risk of suffering EH than homozygotes for M235 or T174 alleles. Associations of AT1 receptor variants with EH remain to be definitively defined. In conclusion, the characterization of the genetic background, although difficult at the present time, may have clear benefits in terms of defining a more rational therapy and prevention in individuals at risk. Even though this aim seems difficult to achieve since more than 150 candidate genes have been postulated as the cause of EH, with 6 to 10 SNPs in each of them, new technologies such as DNA micro-arrays will provide us with the opportunity to analyse the total genetic risk in each subject.
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PMID:[Molecular genetics of essential hypertension. Susceptibility and resistance genes]. 1083 1

Genetic factors play very important role in the pathogenesis of essential hypertension. Angiotensinogen gene is one of the candidate genes in the research concerning genetic background of elevated blood pressure. The aim of this work was to assess an association of M235T polymorphism in human angiotensinogen gene with essential hypertension in Polish population. 250 patients with essential hypertension and 150 normotensives were involved in the study. M235T polymorphism was detected using polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) methods. Polymorphic allele and genotypes frequencies did not differ between hypertensive and normotensive groups. However T allele and TT genotype frequency among hypertensive men was higher than in normotensive men. The difference is statistically significant. T allele and TT genotype occurred more frequently in hypertensives with positive family history of essential hypertension. The difference between hypertensive men with positive family history and normotensive men was even more significant. This results are similar to those already published by other authors concerning Caucasian populations and indicate that angiotensinogen gene is involved in the determination of at least some cases of essential hypertension.
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PMID:[M235T polymorphism of human angiotensinogen gene in essential hypertension in Polish population]. 1107 38

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
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PMID:Effects of the angiotensinogen gene M235T and A(-6)G variants on blood pressure and other vascular risk factors in a Spanish population. 1111 94

Recent advances in genetic determination of human essential hypertension (EHT) are discussed by reviewing the candidate genes. Candidate genes have been selected based on genetic information from classical linkage analysis (affected sib-pair analysis) or mendelian hypertension (autosomal dominant inheritance of hypertension). Most of these genes are, directly or indirectly, coupled to salt handling of the kidney, being included in the renin-angiotensin system (RAS), steroid-hormone metabolism, and renal sodium transporters. Angiotensinogen (AGT) gene in RAS was first described as a strong candidate associated with the onset of hypertension, since sib-pair linkage analysis has demonstrated the trait loci for hypertension which includes the coding region for AGT. M235T polymorphism of AGT has been studied extensively in many populations including Japanese, and the results suggest a weak, but significant linkage with hypertension. The presence (insertion [I]) or absence (deletion [D]) of 287bp in intron 16 of angiotensin converting enzyme gene has also been examined in RAS, and the results suggest D polymorphism as a risk factor for hypertension in men. Other components in RAS, such as renin, angiotensinogen II type I receptor, or kallikrein have also been studied, but the available information is still incomplete. Genetic investigations of mendelian hypertension has identified the genetic mechanisms for glucocorticoid remediable aldosteronism, apparent mineral corticoid excess, and Liddle's syndrome as chimeric gene duplications of CYP11B1 (aldosterone synthase gene) and CYP11B2 (11beta-hydroxylase gene), mutations in the gene of 11beta-hydroxysteroid dehydrogenase type 2 that catalyzes the conversion of cortisol to cortisone, and mutations in beta or gamma subunit of epithelial sodium channel (ENaC), respectively. Subsequently, genetic variants of CYP11B2 and beta or gamma subunit of ENaC have been found, suggesting the -344C polymorphism of CYP11B2, 594S variant of betaENaC, and two rare variants of gammaENaC as risk factors for EHT. In spite of the extensive research, haplotypes in individual populations remain to be elucidcated in most candidate genes. Even casual conclusions of possible linkage with EHT need to be further examined with better determinations of phenotypes, such as ambulatory and home blood pressure monitoring or identification of onset of hypertension in cohort studies.
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PMID:Genetic determination of human essential hypertension. 1112 65

Angiotensinogen (AGT) gene has been regarded as one of the candidate genes for essential hypertension. In our study, the role of AGT gene as a putatively predisposing gene for hypertension was evaluated by genotyping a A (-6) G polymorphism in the core promoter region in 123 patients with essential hypertension and 103 healthy controls. A microchip electrophoresis method coupled with polymorphism chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay was used for genotyping the A (-6) G single-nucleotide polymorphism. The separation and detection of the digested PCR amplicons were completed just in 280 s or less. The genotype frequency fulfilled the criteria of the Hardy-Weinbery equilibrium (X2 = 3.067, P > 0.05). The results showed a higher frequency of the -6 A allele (0.70) in the normotensive subjects, which is higher than those reported in Germany (0.47) and Czech (0.40) populations, but similar to that found in Japanese populations (0.73). The frequencies of genotype AA, AG, and GG were 0.46, 0.49, and 0.05 in hypertensive subjects, and 0.44, 0.53, and 0.03 in control subjects. There is no significant difference in the distributions of the genotype and allele between the two groups (X2 = 0.88, P > 0.05; X2 = 0.024, P > 0.05). These findings differ from some of the results obtained in other ethnic groups, indicating the potential importance of ethnic origin in the assessment of genetic risk identifiers for a complex disease.
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PMID:Genotyping the -6A/G functional polymorphism in the core promoter region of angiotensinogen gene by microchip electrophoresis. 1562 75


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