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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The angiotensinogen M235T polymorphism in humans is linked to differential expression of the human angiotensinogen gene (AGT) gene and hypertension, but the homeostatic responses resulting from this polymorphism are not known. We therefore investigated how mice respond to five genetically determined levels of mouse angiotensinogen gene (Agt) expression covering the range associated with the M235T variants. By using high-throughput molecular phenotyping, tissue RNAs were assayed for expression of 10 genes important in hypertension. Significant positive and negative responses occurred in both sexes as Agt expression increased twofold, including a three-fold increase in aldosterone synthase expression in adrenal gland, and a two-fold decrease in renin expression in kidney. In males, cardiac expression of the precursor of atrial natriuretic peptide B and of adrenomedullin also increased approximately twofold. The relative expression of all genes studied except Agt differed significantly in the two sexes, and several unexpected relationships were encountered. A highly significant correlation between renal expression of the angiotensin type 1a receptor and kallikrein, independent of Agt genotype, is present in females (P < 0.0001) but not males (P = 0.4). The correlation between blood pressure (BP) and liver Agt expression within the five Agt genotypes is significant in females (P = 0.0005) but not in males (P = 0.2), whereas correlation of BP with differences between the genotypes is less in females (P = 0.06) than in males (P = 0.001). The marked gender differences in gene expression in wild-type mice and the changes induced by moderate alterations in Agt expression and BP emphasize the need to look for similar differences in humans.
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PMID:Molecular phenotyping for analyzing subtle genetic effects in mice: application to an angiotensinogen gene titration. 1190 85

Glucocorticoid remediable hyperaldosteronism (GRA) is a monogenic form of inherited hypertension caused by a chimeric gene originating from an unequal cross-over between the 11 beta-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes. GRA is characterized by high plasma levels of aldosterone (regulated by ACTH) with suppressed plasma renin activity and the production of two rare steroids, 18hydroxycortisol and 18oxocortisol. Affected patients usually show severe hypertension and an elevated frequency of stroke at a young age. Affected women have a high risk of developing preeclampsia during pregnancy. Here, we describe a 5-generation pedigree from Sardinia in which the presence of the chimeric gene is demonstrated in 4 generations. This family displays a mild phenotype with average blood pressure levels of 131/86 mm Hg for GRA+ patients. The occurrence of stroke is very low, and preeclampsia was not observed in 29 pregnancies from 8 GRA+ mothers. We investigated whether the cross-over site (between the CYP11B1 and CYP11B2 genes) or biochemical characteristics could explain this phenotype. The cross-over site was located at the end of intron 3, in the same region as described in other families. We found a significant correlation between blood pressure and 18hydroxycortisol, 18oxocortisol, and plasma aldosterone levels, but not with kallikrein. However, none of the biochemical or genetic parameters investigated could explain the mild phenotype of the family.
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PMID:Glucocorticoid remediable aldosteronism: low morbidity and mortality in a four-generation italian pedigree. 1210 22

Primary aldosteronism (PA) is the most common cause of endocrine hypertension. PA is most frequently presented as moderate to severe hypertension, but the clinical and biochemical features vary widely. The aim of our study was to identify genetic variants that influence the phenotype of patients with PA. We hypothesized that genetic variants potentially affecting aldosterone production (aldosterone synthase, CYP11B2), renal proximal tubule reabsorption (alpha-adducin), or the mechanisms of counterbalance leading to vasodilatation and sodium excretion (bradykinin B(2)-receptor, B(2)R) could influence the clinical and biochemical characteristics of patients with PA. We studied three polymorphisms of these genes (C-344T of CYP11B2, G460W of alpha-adducin, and C-58T of B(2)R) in 167 primary aldosteronism patients (56 with aldosterone-producing adenoma and 111 with idiopathic hyperaldosteronism). B(2)R and alpha-adducin genotypes were strong independent predictors of both systolic and diastolic blood pressure levels; plasma renin activity and aldosterone also play a marginal role on BP levels. Body mass index, age, sex, and CYP11B2 genotype displayed no significant effect on the clinical parameters of our population. In particular, alpha-adducin and B(2)R polymorphisms accounted for 13.2% and 11.0% of the systolic and diastolic blood pressure variance, respectively. These data suggest that genetic variants of alpha-adducin and the bradykinin B(2)-R influence the blood pressure levels in patients with primary aldosteronism.
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PMID:Blood pressure in patients with primary aldosteronism is influenced by bradykinin B(2) receptor and alpha-adducin gene polymorphisms. 1210 46

Aldosterone, the major circulating mineralocorticoid, particiates in blood volume and serum potassium homeostasis. Primary aldosteronism is a disorder characterized by hypertension and, in more severe form, hypokalemia, due to autonomous aldosterone secretion from the adrenocortical zona glomerulosa. Improved screening techniques, particularly application of the plasma aldosterone: plasma renin activity ratio, has led to renewed interest in Conn's original proposal that primary aldosteronism may be the cause of increased blood pressure in about 10% of adults with hypertension. Glucocorticoid-remediable aldosteronism (GRA) was the first described familial form of hyperaldosteronism. The disorder is characterized by aldosterone secretory function regulated chronically by ACTH. Hence, aldosterone hypersecretion can be chronically suppressed by exogenous glucocorticoids such as dexamethasone in physiologic-range doses. This autosomal dominant disorder has been shown to be caused by a hybrid gene mutation formed by a cross-over of genetic material between the ACTH-responsive regulatory portion of the 11b-hydroxylase (CYP11B1) gene and the coding region of the aldosterone synthase (CYP11B2) gene. Familial hyperaldosteronism type II (FH-II), so named to distinguish the disorder from GRA or familial hyperaldosteronism type I (FH-I), is characterized by inheritance consistent with an autosomal dominant pattern of autonomous aldosterone hypersecretion which is not suppressible by dexamethasone. Linkage analysis in a single large kindred, and direct mutation screening, has shown that this disorder is unrelated to mutations in the genes for aldosterone synthase or the angiotensin II receptor. A recent genome-wide search has identified a genetic linkage between FH-II in this single large kindred and polymorphic gene markers on chromosome 7 in a region that corresponds to cytogenetic band 7p22. This is the first identified locus for FH-II. Several possible candidate genes have been localized to the 7p22 region. The precise genetic cause of FH-II remains to be elucidated.
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PMID:New genetic insights in familial hyperaldosteronism. 1238 43

The most potent corticosteroids are 11beta-hydroxylated compounds. In humans, two cytochrome P450 isoenzymes with 11beta-hydroxylase activity, catalyzing the biosynthesis of cortisol and aldosterone, are present in the adrenal cortex. CYP11B1, the gene encoding 11beta-hydroxylase (P450c11), is expressed in high levels in the zona fasciculata and is regulated by adrenocorticotropic hormone (ACTH). CYP11B2, the gene encoding aldosterone synthase (P450c11Aldo), is expressed in the zona glomerulosa under primary control of the renin-angiotensin system. The substrate for P450c11 is 11-deoxycortisol. Mutations in CYP11B1 cause congenital adrenal hyperplasia (CAH) due to 11beta-hydroxylase deficiency. This disorder is characterized by androgen excess and hypertension and is autosomal recessively inherited. Classical and nonclassical forms of 11beta-hydroxylase deficiency can be distinguished. Studies in heterozygotes for classical 11beta-hydroxylase deficiency show inconsistent results with no or only mild hormonal abnormalities (elevated plasma levels of 11-deoxycortisol after ACTH stimulation). Molecular genetic studies of the CYP11B1 gene in 11beta-hydroxylase deficiency have led to the identification of several mutations. Transfection experiments showed loss of enzyme activity in vitro. Molecular genetic studies have practical importance for the prenatal diagnosis of virilizing CAH forms.
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PMID:Congenital adrenal hyperplasia: 11beta-hydroxylase deficiency. 1242 5

Predispositions to essential hypertension and cardiovascular diseases are possibly associated with gene polymorphisms of the renin-angiotensin system. Gene polymorphisms of angiotensinogen and angiotensin-converting enzyme genes have been suggested to be risk factors for hypertension and myocardial infarction. Concerning the polymorphism of aldosterone synthase (CYP11B2) gene, earlier studies have shown inconsistent results in terms of its relation to hypertension. In the present case-control study, we investigated the association of -344T/C polymorphism in the promoter region of human CYP11B2 gene with genetic predisposition to hypertension. The genotype of -344T/C polymorphism was determined in essential hypertension subjects (n=250) and normotensive subjects (n=221). The distributions of three genotypes (TT, TC, and CC) were significantly different between the hypertensive and the normotensive groups (chi(2)=9.61, P=0.008). Namely, the frequency of C allele was higher in the hypertensive patients than in the normotensive subjects (34.2 vs 26.5%, P=0.010). Our data suggest that the -344C allele of CYP11B2 gene polymorphism is associated with the genetic predisposition to develop essential hypertension.
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PMID:Positive association of CYP11B2 gene polymorphism with genetic predisposition to essential hypertension. 1244 40

Approximately 10% of patients with hypertension have a high ratio of aldosterone to renin, but the reason for this and the relationships among low-renin essential hypertension, elevation of the ratio, and true primary aldosteronism are unclear. We have previously reported that a polymorphism of the gene (C-to-T conversion at position -344) encoding aldosterone synthase is associated with hypertension, particularly in patients with a high ratio. However, the most consistent association with this variant is a relative impairment of adrenal 11beta-hydroxylation. In this review, we propose that altered conversion of deoxycortisol to cortisol leads to a subtle, chronic increase in adrenocortrophin drive to the adrenal cortex, with eventual development of hyperplasia. In combination with other genetic or environmental factors (such as dietary sodium intake), we suggest that this might be responsible for the long-term development of a resetting of the aldosterone response to angiotensin II, giving rise to the phenotype of hypertension with a raised ratio. In some subjects, this may progress further to true primary aldosteronism with a dominant adrenal nodule. Thus, there may be a genetically influenced continuum from hypertension with a normal ratio, through hypertension with a raised ratio, and primary aldosteronism.
Hypertension 2003 May
PMID:Is altered adrenal steroid biosynthesis a key intermediate phenotype in hypertension? 1265 13

Left ventricular hypertrophy (LVH) is an independent risk factor for morbidity and mortality from cardiovascular disease in men and women with hypertension and in asymptomatic subjects with normal blood pressure. In hypertensive patients it is a stronger coronary risk factor than casual blood pressure readings. Correlation between levels of high blood pressure, duration of hypertension and left ventricular mass is poor. Epidemiological studies suggest that left ventricular hypertrophy may be influenced by genetic factors. In our review we present study groups of genes contributing to the development of left ventricular hypertrophy: 1) genes that encode components of hormonal pathways, 2) genes of key sympathetic and parasympathetic receptors, 3) genes that modify intracellular ion homeostasis, 4) genes that modify energy metabolism, 5) genes that modify motor unit composition and regulation. Angiotensinogen gene, angiotensin-converting enzyme gene, angiotensin receptor type 1 gene, aldosterone synthase gene, nitric oxide synthase gene, type A natriuretic peptide receptor gene, beta(2)-adrenergic receptor gene, G-protein beta(3) subunit gene are associated with left ventricular hypertrophy.
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PMID:[Hereditary factors and left ventricular hypertrophy]. 1289 Dec 90

Excess salt intake is an important environmental risk for the predisposition to essential hypertension. Previous physiological studies have shown that salt sensitivity is associated with insulin resistance, enhancement of sympathetic nerve activity and decrease of blood pressure decline at night. We have been examining the genetic importance of candidate gene polymorphisms of salt-sensitive hypertension using several populations. The angiotensinogen gene (AGT) is a thrifty gene which increases the risk for common disease with growth of civilization via sodium and body fluid retention. The CC genotype of the AGT/T+31C polymorphism, which is in complete linkage disequilibrium with the TT genotype of the M235T polymorphism, was associated with a decrease of blood pressure decline at night in the Ohasama Study. On the other hand, the Gly460Trp genotype of the alpha-adducin gene (ADD1) is associated with erythrocyte sodium transport and increases tubular sodium reabsorption and risk for hypertension. We also revealed in the Ohasama Study that the Trp460 allele of ADD1 is associated with hypertension in young subjects with low renin activity. In addition to these polymorphisms, the T(-344)C polymorphism in the promoter of the aldosterone synthase gene (CYP11B2) and the C825T polymorphism of the G-protein beta3 subunit gene (GNB3) are considered candidates for the genetic risk of salt-sensitive hypertension. We compared the allele frequency of five candidate genes between Japanese and Caucasians; the results showed that the frequencies of all alleles were significantly higher in Japanese than in Caucasians. This interesting finding might suggest a feasible explanation for the huge interracial differences in the frequency of salt-sensitive hypertension.
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PMID:Salt sensitivity of Japanese from the viewpoint of gene polymorphism. 1292 18

To test the effect of increased AT1 receptor expression on blood pressure, we used gene targeting to generate mouse lines with a tandem duplication of the AT1A receptor gene locus (Agtr1a) along with >10 kb of 5' flanking DNA. By successive breeding, we generated mice with 3 and 4 copies of the Agtr1a gene locus on an inbred 129/Sv background. AT1A mRNA expression and AT1-specific binding of 125I-angiotensin II were increased in proportion to Agtr1a gene copy number. These animals survived in expected numbers, and their body, heart, and kidney weights were similar to wild-type, 2-copy control mice. Pressor responses to angiotensin II were blunted in the 4-copy mice compared with control mice. In male mice, there was no correlation between resting blood pressure and Agtr1a gene copy number or AT1A mRNA levels. However, in female mice, there was a highly significant positive correlation between blood pressure and AT1A receptor expression, paralleled by significant increases in aldosterone synthase expression with increase in gene copy number. Furthermore, in female but not male mice, there was a positive correlation between kallikrein and AT1A receptor mRNA levels and an inverse correlation between renin mRNA and Agtr1a copy number. Thus, in female but not male mice, genetic variants that increase expression of AT1 receptors affect blood pressure and gene expression programs. The impact of enhanced AT1 receptor expression on blood pressure may be blunted by systemic compensatory responses and altered signal-effector coupling in the vasculature.
Hypertension 2003 Oct
PMID:Physiological impact of increased expression of the AT1 angiotensin receptor. 1296 78


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