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

Genetic variation in the gene encoding aldosterone synthase (CYP11B2) has previously been shown to be associated with hypertension and left ventricular hypertrophy. The intermediate phenotype most consistently associated with variation at this locus is that of elevated plasma 11-deoxycortisol (S). However, in normal subjects, aldosterone synthase does not metabolize S, which is converted to cortisol (F) by the enzyme 11 beta hydroxylase, encoded by the gene CYP11B1, which lies adjacent to CYP11B2 on chromosome 8. It is possible that the quantitative trait locus for the phenotype is within CYP11B1 and that linkage disequilibrium across the extended locus could account for these observations. However, variation across the whole CYP11B1/B2 locus had not been extensively characterized with respect to these phenotypes. We genotyped six polymorphisms in the CYP11B2 gene and three polymorphisms in the CYP11B1 gene in 248 Caucasian nuclear families comprising 1428 individuals. We measured plasma levels of S and F in 460 individuals from 86 families and urinary excretion rates of tetrahydrodeoxycortisol (THS) and tetrahydrodeoxycorticosterone in 573 individuals from 105 families. We examined heritability of the phenotypes and their association with genotypes and haplotypes at this locus. All steroid phenotypes except urinary tetrahydrodeoxycorticosterone were highly heritable (P < 0.00001). There was strong linkage disequilibrium across the CYP11B1/B2 locus. There was modest evidence for association between polymorphisms of CYP11B2 and plasma levels of S (P = 0.02 for T4986C polymorphism) and the plasma S to F ratio, reflecting the activity of 11-beta hydroxylase (P = 0.01 for T4986C polymorphism). There was strong evidence for association between polymorphisms of both CYP11B1 and CYP11B2 and urinary THS, which was strongest for the CYP11B1 exon 1 polymorphism (P = 0.00002). Addition of other marker data to CYP11B1 exon 1 did not improve the fit of a log-linear model. Genotype at CYP11B1 explained approximately 5% of the variance in urinary THS excretion in the population. Thus, it is likely that linkage disequilibrium between causative CYP11B1 variants and CYP11B2 polymorphisms account for the previous observations. Further fine-mapping studies across the CYP11B1 locus are required to localize the causative variant(s) for the biochemical phenotype; this may also identify susceptibility alleles for hypertension and left ventricular hypertrophy.
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PMID:Genetic variation at the locus encompassing 11-beta hydroxylase and aldosterone synthase accounts for heritability in cortisol precursor (11-deoxycortisol) urinary metabolite excretion. 1552 37

A rare form of congenital adrenal hyperplasia (CAH), 11 beta-hydroxylase deficiency, may be misdiagnosed as 21-hydroxylase deficiency, the most common form of CAH, because of similar clinical presentations at times and elevated level of 17-hydroxyprogesterone in both conditions. We report a case of 11 beta-hydroxylase deficiency that was originally misdiagnosed as 21-hydroxylase deficiency. Hypertension and hypokalemia complicated with seizures and arrhythmia developed in this 9-year-old girl after abrupt withdrawal of oral dexamethasone but maintenance of fludrocortisone. Suspicion of 11 beta-hydroxylase deficiency led to DNA mutation analysis, which revealed a novel point mutation (CTG 461 CCG) in the CYP11B1 gene converting leucine to proline. Her condition stabilized rapidly after withdrawal of fludrocortisone and administration of hydrocortisone. Regular measurement of blood pressure should be performed in all patients with CAH and test of serum 11-deoxycortisol or deoxycorticosterone level should be performed in those patients with elevated blood pressure to avoid misdiagnosis of 11 beta-hydroxylase deficiency.
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PMID:Congenital adrenal hyperplasia with 11 beta-hydroxylase deficiency. 1554 55

The so-called essential hypertension is not a single entity but a mixed bag with several polygenic quantitative traits acting in concert in different combinations in different individuals. This review collates all published information from different centres using different approaches to identify candidate genes in human hypertension. 1) gene targeting approach in animal models of HT (Smithies and Maeda, 1995); 2) identification of 874 candidate SNPs in 75 candidate genes for human HT (Halushka et al, 1999); 3) comparative genomic approach translating QTLs between rat and human HT, to identify 26 chromosome regions on 16 autosomes (Stoll M et al, 2000); 4) Ten centimorgan genome-wide scan done on 2010 affected sibling pairs drawn from 1599 severely hypertensive families (Caulfield et al, 2003). The molecular mechanisms of various molecules involved in the homeostasis of blood pressure are discussed. NO, O2, PG12, EDHF, endothelin, IL-6, selectin, phospholipase A2G1B, BH4, SOD, IRS-1, adrenomedullin, PAMP, CGRP, ANP, bradykinin and bombesin; adducin alpha, beta, gamma, SAH, renin, angiotensinogen. angiotensin II, aldosterone CYP11B1, mineralocorticoid receptors, 11betaHSD, DBH, PNMT, beta2adrenoreceptors, and genes related to ion transport-sodium-lithium cotransporters, ENaC, NaCl cotransporters NKCC2, KCNJ and NaKATPase. Altered gene expression in fetus due to maternal malnutrition also "programmes" for adult hypertension.
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PMID:Hypertension: molecular approach. 1563 21

11beta-Hydroxylase deficiency is a common form of congenital adrenal hyperplasia causing virilization of the female fetus and hypertension. DNA analysis of the gene (CYP11B1) encoding 11beta-hydroxylase has been reported previously to be effective in the prenatal diagnosis of one affected female fetus. In that case, prenatal treatment with dexamethasone resulted in normal female genitalia. We now report five new pregnancies that underwent prenatal diagnosis for 11beta-hydroxylase deficiency. In the first family, the proband is homozygous for a T318M mutation and all fetuses from four subsequent pregnancies are carriers. In a second family, the mother is homozygous for a A331V mutation and was started on dexamethasone, but identification of a homozygous normal fetus led to the discontinuation of treatment. In another family, the fetus was a male homozygous for R384Q and treatment was discontinued. Lastly, a novel G444D mutation in exon 8 was identified and proven to reduce 11beta-hydroxylase activity.
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PMID:Update on the prenatal diagnosis and treatment of congenital adrenal hyperplasia due to 11beta-hydroxylase deficiency. 1575 2

Congenital adrenal hyperplasia due to 11beta-hydroxylase enzyme deficiency is a result of the impairment of 11-deoxycortisol to cortisol conversion. In general, it is responsible for less than 5% of the congenital adrenal hyperplasia cases. The clinical expression of androgen excess in females includes several degrees of genital ambiguity, varying from clitoromegaly to complete virilization. Due to the accumulation of mineralocorticoids, approximately 50% of the patients develop blood hypertension. Mutations in the CYP11B1 gene are responsible for the disease. Biochemical and molecular characteristics of the enzyme and their implications in the clinical presentation of 11beta-hydroxylase deficiency are reviewed here.
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PMID:[11beta-hydroxylase deficiency]. 1576 43

Glucocorticoid-remediable aldosteronism (GRA), also known as familial hyperaldosteronism type I (FH-I, OMIM 103900), is a monogenic form of inherited hypertension caused by the presence of a chimaeric gene originating from an unequal cross-over between the CYP11B1 (11beta-hydroxylase) and CYP11B2 (aldosterone synthase) genes. The hybrid gene has the CYP11B1 sequence at the 5' end, including the promoter, and the CYP11B2 sequence at the 3' end. The aim of our study was to evaluate the prevalence of GRA in a Polish population of 129 patients with primary hyperaldosteronism (PHA) and 132 patients with essential hypertension (EH), through the use of a PCR-based test revealing the chimaeric gene. None of our PHA or EH patients was positive for the CYP11B1/CYP11B2 chimaeric gene. These data suggest that GRA is unlikely to be a common cause of hypertension in Polish subjects. However, the real prevalence of GRA in Poland, both in the high-risk group of individuals with primary hyperaldosteronism and in the general population, remains to be established.
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PMID:Genetic screening for glucocorticoid-remediable aldosteronism (GRA): experience of three clinical centres in Poland. 1611 Jan 93

Steroid hormone biosynthesis is catalyzed by the action of a series of cytochrome P450 enzymes as well as reductases. Defects in steroid hydroxylating P450s are the cause of several severe defects such as the adrenogenital syndrome (AGS), corticosterone methyl oxidase (CMO) I or II deficiencies, or pseudohermaphroditism. In contrast, overproduction of steroid hormones can be involved in breast or prostate cancer, in hypertension, and heart fibrosis. Besides inhibiting the action of the steroid hormones on the level of steroid hormone receptors by using antihormones, which often is connected with severe side effects, more recently the steroid hydroxylases themselves turned out to be promising new targets for drug development. Since the 3-dimensional structures of steroid hydroxylases are not yet available, computer models of the corresponding CYPs may help to develop new inhibitors of these enzymes. During the past years, the necessary test systems have been developed and new compounds have been synthesized, which displayed selective and specific inhibition of CYP17, CYP11B2, and CYP11B1. With some of these potential new drugs, clinical trials are under way. It can be expected that in the near future some of these compounds will contribute to our arsenal of new and selective drugs.
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PMID:CYP17- and CYP11B-dependent steroid hydroxylases as drug development targets. 1642 83

The -344 C/T and intron 2 conversion variants in the CYP11B2 gene, encoding aldosterone synthase, have been associated with markers of impaired 11beta-hydroxylase activity. We hypothesize that this association is because of variations in the adjacent 11beta-hydroxylase gene (CYP11B1) and arises through linkage disequilibrium between CYP11B1 and CYP11B2. The pattern of variation across the entire CYP11B locus was determined by sequencing 26 normotensive subjects stratified by and homozygous for the -344 and intron conversion variants. Eighty-three variants associated with -344 and intron conversion were identified. Haplotype analysis revealed 4 common haplotypes, accounting for 68% of chromosomes, confirming strong linkage disequilibrium across the region. Two novel CYP11B1 polymorphisms upstream of the coding region (-1889 G/T and -1859 A/G) were identified as contributing to the common haplotypes. Given the potential for such mutations to affect transcriptional regulation of CYP11B1, these were analyzed further. A total of 512 hypertensive subjects from the British Genetics of Hypertension Study population were genotyped for these polymorphisms. A significant association was identified between the -1889 polymorphism and urinary tetrahydrodeoxycortisol/total cortisol metabolite ratio, indicating reduced 11beta-hydroxylase efficiency. A similar pattern was observed for the -1859 polymorphism, but this did not achieve statistical significance. Functional studies in vitro using luciferase reporter gene constructs show that these polymorphisms significantly alter the transcriptional response of CYP11B1 to stimulation by adrenocorticotropic hormone or forskolin. This study strongly suggests that the impaired 11beta-hydroxylase efficiency associated previously with the CYP11B2 -344 and intron conversion variants is because of linkage with these newly identified polymorphisms in CYP11B1.
Hypertension 2007 Jan
PMID:Polymorphic variation in the 11beta-hydroxylase gene associates with reduced 11-hydroxylase efficiency. 1707 29

Aldosterone plays essential roles in body fluid and electrolyte homeostasis and blood pressure. However, the association between polymorphisms in the CYP11B2 gene and hypertension is controversial. We resequenced CYP11B1 and CYP11B2 and identified 35 polymorphisms in this region. We performed association studies between the plasma aldosterone concentration and 13 polymorphisms in this region in 1443 subjects. The subjects were all obtained from the Suita Cohort Study. Multiple regression analysis indicated that aldosterone levels were determined by renin activity, age, total cholesterol, and hematocrit. Residuals of the aldosterone levels after adjusting for these confounding factors were nominally associated with the T(-344)C (P=0.0026), C(595)T (P=0.0180), -(4837)C (P=0.0310), and G(4936)A (P=0.0498) polymorphisms. Only the T(-344)C polymorphism was significantly associated with the aldosterone level after a correction for multiple testing (Bonferroni). A significant interaction was observed between the T(-344)C polymorphism and renin activity in determining aldosterone levels. Moreover, a significant interaction was observed in 2063 subjects between urinary sodium excretion, which reflects sodium intake, and the T(-344)C polymorphism in determining systolic blood pressure. Only subjects with the TT genotype showed a positive correlation between urinary sodium excretion and systolic blood pressure. In vitro experiments confirmed the functional significance of this T(-344)C polymorphism in terms of angiotensin II reactivity. Thus, the T(-344)C polymorphism in CYP11B2 appears to affect salt sensitivity in Japanese and to have clinical significance.
Hypertension 2007 Apr
PMID:Polymorphism of CYP11B2 determines salt sensitivity in Japanese. 1729 72

11 beta-Hydroxylase deficiency is a rare form of congenital adrenal hyperplasia, resulting in virilization, glucocorticoid deficiency and hypertension. There have been no previous reports in the literature of a successful pregnancy in a severely affected female. We report the first successful pregnancy resulting in a live birth for a female with 11 beta-hydroxylase deficiency and outline management issues from preconception to successful birth. We also report 2 novel mutations in the CYP11B1 gene leading to 11 beta-hydroxylase deficiency.
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PMID:Successful pregnancy in a patient with severe 11-beta-hydroxylase deficiency and novel mutations in CYP11B1 gene. 1772 34


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