Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.23.15 (renin)
35,795 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We sought to determine whether genes of the renin-angiotensin-aldosterone system can predict the nonmodulating intermediate phenotype in essential hypertension. Aldosterone responses to angiotensin II were assessed in 298 subjects with hypertension. Subjects were genotyped at the angiotensinogen M235T, angiotensin-converting enzyme I/D, aldosterone synthase C-344 T, renin, angiotensin II type 1 receptor, and adducin loci. The data were analyzed by Student t test, ANOVA, stepwise linear regression and general linear model or GENMOD regression techniques, and chi2 analysis odds ratios (ORs). Aldosterone response varied by genotype for angiotensin and aldosterone synthase but not for the other loci. The combination of angiotensinogen 235 TT and angiotensin-converting enzyme DD showed further reduction (P=0.0377) when compared with angiotensinogen 235 TT alone, an example of genetic epistasis. When the subject was required also to possess the CYP11B2 -344 TT genotype, there was a further substantial reduction. Of these 3 loci, only angiotensinogen 235 TT significantly increased the OR of predicting the nonmodulating hypertensive phenotype (OR, 2.00; 95% confidence interval, 1.152 to 3.51). However, when angiotensin-converting enzyme DD was combined with angiotensinogen 235 TT, the OR nearly doubled to 3.74, with a further increase to 5.36-fold when the subject possessed all 3 genotypes. Thus, the angiotensinogen, angiotensin-converting enzyme, and aldosterone synthase genotypes identified individuals with the nonmodulating phenotype with an increasing degree of fidelity. For this subclass of essential hypertension, it is likely that genotyping can be substituted for complex phenotyping for therapeutic and preventive decision making.
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PMID:Genetic determinants of nonmodulating hypertension. 1453 Feb 92

Genes of the renin-angiotensin-aldosterone system (RAAS) are natural candidates for sodium homeostasis and blood pressure regulation. To investigate the effect of a combination of polymorphisms of RAAS genes on renal sodium handling and blood pressure, 918 participants to the Olivetti Heart Study were genotyped for the following polymorphisms: I/D of angiotensin converting enzyme (ACE), M235T of angiotensinogen (AGT), A1166C of angiotensin II type-1 receptor (AT1R), and C-344T of aldosterone synthase (CYP11B2). The segmental renal sodium handling was evaluated by the fractional excretions of exogenous lithium (FE-Li), uric acid (FE-UA), and sodium (FE-Na). Twenty-eight carriers of triple homozygosity for M (AGT), A (AT1R), and C (CYP11B2) in the presence of the D allele of ACE (DD/ID) showed lower FE-Li (20.0%+/-5.9% versus 25.0%+/-7.5%; P=0.004; mean+/-sD), FE-UA (6.3%+/-2.0% versus 8.2%+/-2.7%; P=0.001), and FE-Na (0.96%+/-0.41% versus 1.22%+/-0.61%; P=0.004) as compared with all other allelic combinations (n=890), independently from age and body mass, suggesting an enhanced rate of proximal tubular sodium reabsorption. The carriers of the MM, AA, CC, DD/ID combination showed a substantially higher probability of being hypertensive (OR: 3.4 [(99% CI: 1.1 to 10.1]), independently of age and body mass. This relatively rare combination of allelic variants of candidate genes of the RAAS is associated with a significant alteration in proximal renal sodium handling and with higher risk of hypertension, suggesting that a combination of polymorphic variants at different candidate loci may affect phenotypic expression even in the absence of detectable effects of each variant at any single locus.
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PMID:Combination of renin-angiotensin system polymorphisms is associated with altered renal sodium handling and hypertension. 1496 47

The terminal stages in the synthesis of aldosterone and cortisol are catalysed by the enzymes aldosterone synthase and 11beta-hydroxylase respectively. We have previously reported that polymorphic variation in the 5' promoter region (-344C/T) of the gene encoding aldosterone synthase (CYP11B2) is associated with increased aldosterone metabolite excretion and with hypertension associated with a raised aldosterone to renin ratio (ARR). Additionally, basal and ACTH-stimulated plasma levels of 11-deoxycortisol, the precursor of cortisol, are higher in subjects carrying the T-allelic variant. We have now identified in a family study (573 individuals from 105 extended families ascertained through a hypertensive proband) that excretion of the main metabolite of this steroid (tetrahydro-11-deoxycortisol, THS) is heritable (19.4%) and that the T-allele of CYP11B2 is more strongly associated with higher THS levels than the C-allele. Raised plasma and urinary levels of 11-deoxycortisol suggest that there is relative inefficiency of 11beta-hydroxylation in the zona fasciculata; the P450 enzyme responsible for this step is encoded by the gene CYP11B1, which is highly homologous with and adjacent to CYP11B2. The association of genetic variation in the promoter of CYP11B2 which, in the adrenal cortex, is only expressed in zona glomerulosa, and zona fasciculata 11beta-hydroxylation function is paradoxical. There may be linkage dys-equilibrium between this polymorphism and a quantitative trait locus (QTL) in CYP11B1. Chronic alteration of 11beta-hydroxylase activity may increase ACTH drive to the adrenal cortex, altering the regulation of aldosterone synthesis. This may explain, at least partly, the association between CYP11B2 polymorphisms and hypertension.
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PMID:The impact of polymorphisms in the gene encoding aldosterone synthase (CYP11B2) on steroid synthesis and blood pressure regulation. 1513 24

The blood pressure (BP) response to any single antihypertensive drug is characterized by marked interindividual variation, and the known predictors of response are of limited value in identifying the optimum drug for an individual patient. Analysis of genetic variation has the potential to improve our understanding of determinants of antihypertensive drug response in order to individualize drug selection. Genetic variation can influence both pharmacokinetic and pharmacodynamic mechanisms underlying variation in drug response. Classic pharmacogenetic investigations have identified variations in single genes that have a large effect on antihypertensive drug metabolism and are inherited in a Mendelian fashion. These include a polymorphism in the CYP2D6 gene, encoding a cytochrome p450 family member involved in phase I drug metabolism, and polymorphisms in genes encoding enzymes involved in phase II drug metabolism, including N-acetyltransferase (NAT2), catechol-O-methyltransferase (COMT), and phenol sulfotransferase (P-PST, SULT1A1). Although these polymorphisms have major effects on the pharmacokinetic profiles of both commonly used antihypertensive drugs such as metoprolol (CYP2D6), and lesser used drugs such as hydralazine (NAT2), methyldopa (COMT), and minoxidil (SULT1A1), they have not been shown to influence variation in the antihypertensive effect of these drugs at conventional doses. Interest is now focused on identifying genetic polymorphisms that influence the pharmacodynamic determinants of antihypertensive response. Using a candidate gene approach, such polymorphisms have been identified in genes encoding alpha-adducin (ADD1), subunits of G-proteins (GNB3 and GNAS1), the beta(1)-adrenergic receptor (ADRB1), endothelial nitric oxide synthase (NOS3), and components of the renin-angiotensin-aldosterone system (angiotensinogen [AGT], angiotensin converting enzyme [ACE], the angiotensin type I receptor [AGTR1], and aldosterone synthase [CYP11B2]). These polymorphisms have been shown to influence the BP response to diuretics (ADD1, GNB3, NOS3, and ACE), beta-blockers (GNAS1 and ADRB1), ACE inhibitors (AGT, ACE, and AGTR1), angiotensin receptor blockers (ACE and CYP11B2), and clonidine (GNB3).An emerging consensus from these studies is that single gene effects on antihypertensive drug responses are small, and even the combined effects of all presently known polymorphisms do not account for enough variation in response to be clinically useful. New genome-wide scanning techniques may lead to the identification of genes previously unsuspected of influencing drug response. Additional requirements for pharmacogenetic approaches to become clinically useful are the characterization of the effects of haplotypes and multi-locus genotypes on drug response, and consideration of gene-by-environment interactions. Such studies will require huge sample sizes and novel statistical methods, but the theoretical and technical framework is in place to make this possible.
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PMID:Pharmacogenetics of antihypertensive drug responses. 1517 96

The T(-344)C polymorphism in promoter of CYP11B2 gene encoding aldosterone synthase has been associated with differences in plasma aldosterone (ALDO) concentrations. In addition, the results of recent study carried out in Japan suggest that C(-344) allele of CYP11B2 may be a genetic marker of salt-sensitive hypertension characterized by low plasma renin activity (PRA) and high ALDO/PRA ratio. Therefore, it raises the question of whether the T(-344)C polymorphism of CYP11B2 gene may be associated with salt-sensitive hypertension in Caucasians. The DNA samples were obtained from 68 Polish hypertensives. During 3 subsequent 1-week periods each subject received diets of normal, low and high sodium content (120-140, 20-40 and 240-260 mmol Na+/day, respectively). Salt sensitivity was expressed as the difference between mean arterial pressure (MAP) on high salt diet and MAP on low salt one (delta MAPH-L). Genomic DNA isolated from peripheral blood nuclear cells was amplified by PCR method with primers flanking the polymorphic region and C(-344) allele was identified by gain of Hae III restriction site. There were 14 TT homozygotes (20.6%), 35 TC heterozygotes (51.5%) and 19 CC homozygotes (27.9%) in the studied group. No significant differences in delta MAPH-L, glomerular filtration rate, natriuresis, excreted fraction of filtered sodium, PRA, ALDO and ALDO/PRA ratio determined on each diet have been found in subjects according to CYP11B2 genotype. Our preliminary results suggest the lack of association of the T(-344)C CYP11B2 polymorphism with salt-sensitive hypertension as well as with activity of plasma renin-angiotensin-aldosterone system in Caucasian patients.
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PMID:[Promoter variants of aldosterone synthase gene (CYP11B2) and salt-sensitivity of blood pressure]. 1523 Feb 31

Sympathetic tone increases with stimulation of the renin-angiotensin system and is under the influence of salt intake. In the European Project On Genes in Hypertension (EPOGH), we investigated whether polymorphisms in the genes encoding aldosterone synthase (CYP11B2 C-344T) and the type-1 angiotensin II receptor (AT1R A1166C) affect the autonomic modulation of heart rate at varying levels of salt intake. We measured the low frequency (LF) and high frequency (HF) components of heart rate variability and their ratio (LF:HF) in the supine and standing positions in 1797 participants (401 families and 320 unrelated subjects) randomly selected from 6 European populations, whose average urinary sodium excretion ranged from 163 to 245 mmol/d. In multivariate analyses with sodium excretion analyzed as a continuous variable, we explored the phenotype-genotype associations using generalized estimating equations and quantitative transmission disequilibrium tests. Across populations, there was no heterogeneity in the phenotype-genotype relations. The genotypic effects differed according to sodium excretion. In subjects with sodium excretion <190 mmol/d (median), supine heart rate, LF, and LF:HF increased and HF decreased with the number of CYP11B2 -344T alleles, and the orthostatic changes in LF, HF, and LF:HF were blunted in carriers of the AT1R 1166C allele. In subjects with sodium excretion >190 mmol/d, these associations with the CYP11B2 and AT1R polymorphisms were nonsignificant or in the opposite direction, respectively. Thus, CYP11B2 C-344T and AT1R A1166C polymorphisms affect the autonomic modulation of heart rate, but these genetic effects depend on sodium excretion.
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PMID:Genetic variation in CYP11B2 and AT1R influences heart rate variability conditional on sodium excretion. 1523 68

Aldosterone synthase deficiency (ASD) usually presents in infancy as a life-threatening electrolyte imbalance. A 4-wk-old child of unrelated parents was examined for failure to thrive and salt-wasting. Notable laboratory findings were hyperkalemia, high plasma renin, and low-normal aldosterone levels. Urinary metabolite ratios of corticosterone/18-hydroxycorticosterone and 18-hydroxycorticosterone/aldosterone were intermediate between ASD type I and type II. Sequence analysis of CYP11B2, the gene encoding aldosterone synthase (P450c11AS), revealed that the patient was a compound heterozygote carrying a previously described mutation located in exon 4 causing a premature stop codon (E255X) and a further, novel mutation in exon 5 that also causes a premature stop codon (Q272X). The patient's unaffected father was a heterozygous carrier of the E255X mutation, whereas the unaffected mother was a heterozygous carrier of the Q272X mutation. Therefore, the patient's CYP11B2 encodes two truncated forms of aldosterone synthase predicted to be inactive because they lack critical active site residues as well as the heme-binding site. This case of ASD is of particular interest because despite the apparent lack of aldosterone synthase activity, the patient displays low-normal aldosterone levels, thus raising the question of its source.
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PMID:A particular phenotype in a girl with aldosterone synthase deficiency. 1524 May 89

Hypertension is a common disorder that affects a large heterogeneous patient population. Subgroups can be identified on the basis of their responses to hormonal and biologic stimuli. These subgroups include low-renin hypertensives and nonmodulators. Aldosterone, the principal human mineralocorticoid, is increasingly recognized as playing a significant role in cardiovascular morbidity, and its role in hypertension has recently been reevaluated with studies that suggest that increased aldosterone biosynthesis (as defined by an elevated aldosterone to renin ratio) is a key phenotype in up to 15% of individuals with hypertension. It was reported previously that a polymorphism of the gene (C to T conversion at position -344) encoding aldosterone synthase is associated with hypertension, particularly in individuals with a high ratio. However, the most consistent association with this variant is a relative impairment of adrenal 11beta-hydroxylation. This review explores the evidence for this and provides a hypothesis linking impaired 11beta-hydroxylation and hypertension with a raised aldosterone to renin ratio. It is also speculated that there is substantial overlap between this group of patients and previously identified low-renin hypertensives and nonmodulators. Thus, these groups may form a neurohormonal spectrum reflecting different stages of hypertension or indeed form sequential steps in the natural history of hypertension in genetically susceptible individuals.
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PMID:Mechanisms of hypertension: the expanding role of aldosterone. 1528 85

Primary aldosteronism is a disorder characterized by hypertension and hypokalemia due to aldosterone secretion out of renin-angiotensin control. It is generally caused by aldosterone-producing adenoma or adrenocortical hyperplasia but, in some cases, it is due to genetic alterations. Familial type I hyperaldosteronism is the result of anomalous regulation of aldosterone secretion from ACTH (which normally regulates cortisol synthesis). Aldosterone hypersecretion can be suppressed by exogenous glucocortcoids such as dexamethasone. This autosomal dominant disorder is caused by unequal cross-over between two genes with wide sequence homology: CYP11B1 and CYP11B2. The hybrid gene is the product of fusion between the ACTH-responsive regulatory portion of the 11b-hydroxylase gene (CYP11B1) and the coding region of the aldosterone synthase gene (CYP11B2). Familial type I hyperaldosteronism is a disease with incomplete penetration and variable expressivity, especially in relation to hypertension. The marked variability in hypertension severity can mirror an interaction between the hybrid gene and other hereditary factors involved in the regulation of blood pressure. Familial type II hyperaldosteronism is another autosomal dominant form of hyperaldosteronism due to aldosterone hyper-secretion not suppressible by dexamethasone. This disorder is unrelated to mutation of the hybrid gene. The genetic cause of type II hyperaldosteronism is presently unknown, but a genome-wide search has revealed that the disorder is linked with a locus on chromosome 7 in a region that corresponds to cytogenetic band 7p22.
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PMID:[Familial hyperaldosteronism]. 1535 48

Reduced adrenal 11 beta-hydroxylation has been associated with an aldosterone synthase (CYP11B2) polymorphism. The 11 beta-hydroxylase gene (CYP11B1) lies close to CYP11B2. We hypothesize that a molecular variant in CYP11B2 is in linkage disequilibrium (LD) with a key quantitative trait in CYP11B1 determining this phenotype. Polymorphisms and inferred haplotypes at CYP11B loci were studied in two independent populations from Europe (n = 100) and South America (n = 99). The latter underwent detailed hormonal studies. LD was estimated by alternative Bayesian methods for inferring the extent of LD when haplotypes at different loci are inferred. Population differences in single nucleotide polymorphisms were modest, indicating the stability of both genes across populations. Using five of nine potentially informative loci at CYP11B sites with allele frequency greater than 0.1, two major contrasting haplotypes, CwtCG and TconvGTA, were found. In both populations the CwtCG haplotype accounted for 44% and the TconvGTA for 32% of subjects. Haplotype distribution did not differ between Europeans and South Americans (chi(2) = 2.81; P = 0.09). In vivo 11 beta-hydroxylase activity, estimated from urinary steroid profiling, was lower in subjects with an increased aldosterone to renin ratio or with the TconvGTA haplotype. These findings indicate that genotypes at the CYP11B locus are in strong LD and that identified haplotypes predict 11 beta-hydroxylase activity.
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PMID:CYP11B2-CYP11B1 haplotypes associated with decreased 11 beta-hydroxylase activity. 1550 9


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