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)

Mutations of the last exon of the beta subunit of the amiloride-sensitive epithelial Na+ channel (betaENaC) can lead to Liddle's syndrome, a rare monogenic form of hypertension. The objective of this study was to test whether more subtle changes of betaENaC could be implicated in essential hypertension. After determination of the betaENaC coding gene organization (12 exons spanning 23.5 kb), a systematic screening of the last exon of the gene was performed in 525 subjects (475 whites, 50 Afro-Caribbeans), all probands of hypertensive families. This search was extended to the remaining 11 exons in a subset of 101 probands with low-renin hypertension. Seven amino acid changes were detected: G589S, T594M, R597H, R624C, E632G (last exon), G442V, and V434M (exon 8). These genetic variants were more frequent in subjects of African origin (44%) than in whites (1%). The functional properties of the variants were analyzed in Xenopus oocytes by two independent techniques, ie, electrophysiology and 22Na+ uptake. Small but not significant differences were observed between the variants and wild type. The clinical evaluation of the family bearing the G589S variant, which provided the highest relative ENaC activity, did not show a cosegregation between the mutation and hypertension. The present study illustrates the difficulty in establishing a relation of causality between a susceptibility gene and hypertension. Furthermore, it does not favor a substantial role of the betaENaC gene in essential hypertension.
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PMID:Genetic analysis of the beta subunit of the epithelial Na+ channel in essential hypertension. 967 49

Data obtained during the last two decades show that spontaneously hypertensive rats, an acceptable experimental model of primary human hypertension, possess increased activity of both ubiquitous and renal cell-specific isoforms of the Na+/H+ exchanger (NHE) and Na+-K+-2Cl- cotransporter. Abnormalities of these ion transporters have been found in patients suffering from essential hypertension. Recent genetic studies demonstrate that genes encoding the beta- and gamma-subunits of ENaC, a renal cell-specific isoform of the Na+-K+-2Cl- cotransporter, and alpha3-, alpha1-, and beta2-subunits of the Na+-K+ pump are localized within quantitative trait loci (QTL) for elevated blood pressure as well as for enhanced heart-to-body weight ratio, proteinuria, phosphate excretion, and stroke latency. On the basis of the homology of genome maps, several other genes encoding these transporters, as well as the Na+/H+ exchanger and Na+-K+-2Cl- cotransporter, can be predicted in QTL related to the pathogenesis of hypertension. However, despite their location within QTL, analysis of cDNA structure did not reveal any mutation in the coding region of the above-listed transporters in primary hypertension, with the exception of G276L substitution in the alpha1-Na+-K+ pump from Dahl salt-sensitive rats and a higher occurrence of T594M mutation of beta-ENaC in the black population with essential hypertension. These results suggest that, in contrast to Mendelian forms of hypertension, the altered activity of monovalent ion transporters in primary hypertension is caused by abnormalities of systems involved in the regulation of their expression and/or function. Further analysis of QTL in F2 hybrids of normotensive and hypertensive rats and in affected sibling pairs will allow mapping of genes causing abnormalities of these regulatory pathways.
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PMID:Genetic and biochemical determinants of abnormal monovalent ion transport in primary hypertension. 1006 78

The candidate gene approach to understanding the genetics of human essential hypertension is discussed by analyzing the contribution of 2 genes, angiotensinogen (AGT) and epithelial amiloride-sensitive sodium channel (ENaC). From a large series of studies conducted in humans and animals, it appears that the AGT gene plays a significant but modest role in human blood pressure variance. Mutations of the beta- and gamma-ENaC subunits are responsible for Liddle's syndrome, but the implication of the 3 ENaC subunits in essential hypertension is still questionable. Several lessons can be learned from these studies and applied to other candidate genes in essential hypertension: (1) Many linkage or association studies have a limited statistical power; (2) The genetic findings may vary greatly according to the populations studied; (3) There is a need for better phenotyping of the hypertensive population; (4) The causal relationship between molecular variants and hypertension is and will be difficult to establish firmly; (5) The contribution of genetic studied in rodents to the molecular genetics of human hypertension must be re-examined; (6) Most molecular variants lead to a low attributable risk in the population or a low individual effect at the individual level; and (7) It is too early to propose dietary recommendations and specific drug treatment according to patients' genotypes.
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PMID:Seven lessons from two candidate genes in human essential hypertension: angiotensinogen and epithelial sodium channel. 1037 10

Previous studies of hypertension in humans and experimental animal models have identified a number of candidate genes that have since been implicated as possibly contributing to essential hypertension. Among them are the genes encoding angiotensinogen, renin, the beta- and gamma-subunits of the epithelial sodium channel (beta/gamma-ENaC), alpha-adducin, and kallikrein (KLK). To examine the role of possible contribution of these genes in ethnic Chinese, as well as the epistatic interaction among them, we studied a large cohort of hypertensive sib pairs from China. DNA samples from 310 concordant affected sibling pairs with hypertension were tested for linkage with the use of excess allele-sharing algorithms based on genotyping with highly informative GT-repeat microsatellite markers localized in the immediate vicinity of the genes encoding angiotensinogen, renin, beta- and gamma-ENaC, alpha-adducin, and KLK. Affected sib pair analysis conducted according to 3 different methods (Statistical Analysis for Genetic Epidemiology [S.A.G.E. ]/SIBPAL, MAPMAKER/SIBS, and affected pedigree member [APM] methods) revealed no evidence for linkage of any of these genes to primary hypertension in the population studied. Moreover, 2-locus sib pair linkage analyses to test for gene-gene interactions among each possible pair of candidate genes failed to yield any statistically significant results. Our findings provide no support for a significant contribution of the angiotensinogen, renin, beta/gamma-ENaC, alpha-adducin, or KLK genes, alone or in concert, to the pathogenesis of essential hypertension among Chinese. Our results emphasize the possible role of ethnic differences for complex disease genetics, as well as the need for large, well-characterized investigations.
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PMID:Linkage analysis of candidate genes and gene-gene interactions in chinese hypertensive sib pairs. 1037 11

We evaluated the association of a common polymorphism in gammaENaC, consisting in a C to G transversion in codon 649, with essential hypertension and to the pressor response to salt in whites. Two hundred fifteen essential hypertensive patients, and 137 normotensive controls were genotyped for the gamma649 ENaC polymorphism by polymerase chain reaction method and diagnostic restriction enzyme digestion. The genotype distribution of the gamma649 ENaC polymorphism in the hypertensives, 129 CC (60%) and 86 CG/GG (40%) was not significantly different from that of the control group, 84 CC (61%) and 53 CG/GG (39%) (P = .81). Salt sensitivity was assessed in a group of 48 patients by 24-h mean blood pressure response to changes in salt intake. Nineteen patients were diagnosed as salt sensitive, whereas 29 had salt-resistant hypertension. The gamma649 ENaC genotype distribution in salt-sensitive patients was 12 CC (63%) and 7 CG/GG (37%), not significantly different from the distribution in the salt-resistant group, 19 CC (65%) and 10 CG/GG (35%), P = .87. The changes in systolic, diastolic, and mean blood pressure as measured by ambulatory blood pressure monitoring, and in plasma renin activity and plasma aldosterone induced by high salt diet were not different among the gamma649 ENaC genotypes. In the present study we found no association between the gamma649 ENaC polymorphism and essential hypertension or salt sensitivity. Although these data do not support a major causative role for this polymorphism, we cannot exclude that a functional mutation elsewhere in ENaC might be associated with essential hypertension.
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PMID:Genetic variation of the gamma subunit of the epithelial Na+ channel and essential hypertension. Relationship with salt sensitivity. 1091 48

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

Low-renin hypertension is common and usually implies increased retention of sodium (Na(+)). In every case of known etiology, there is a mineralocorticoid-induced increase in number of epithelial Na(+) channels (ENaCs) in the collecting duct of the kidney, leading to a state of "hyperENaCactivity." In primary aldosteronism, a result of either an adrenal adenoma or bilateral adrenal hyperplasia, aldosterone itself mediates the increase in ENaC function. A severe form of low-renin hypertension in which a molecular mutation in ENaC prevents removal of the channel from the cell surface, known as Liddle's syndrome, results in increased net ENaC activity but, in this case, independently of an increase in aldosterone. Glucocorticoid remedial aldosteronism, an autosomal dominant form of primary aldosteronism, results from a "new" or chimeric gene for aldosterone synthase. Adrenocorticotropic hormone stimulates its expression as well as secretion of aldosterone. Apparent mineralocorticoid excess results from a molecular mutation that allows cortisol to bind to the mineralocorticoid receptor. Both glucocorticoid remedial aldosteronism and apparent mineralocorticoid excess result in an increase in the number of ENaCs. The question remains whether low-renin essential hypertension is related to an increase in ENaC activity. Low-renin hypertension is most common in black patients, who tend to have lower levels of aldosterone as well as renin, which are features that resemble those found in Liddle's syndrome. Preliminary findings suggest that black patients with low-renin hypertension who are resistant to standard antihypertensive therapy respond favorably to the addition of spironolactone, a mineralocorticoid receptor antagonist that reduces ENaC activity.
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PMID:Low-renin hypertension: more common than we think? 1117 96

Essential or primary hypertension is a multifactorial disease that is expressed as a result of complex interactions between genes and environmental influences. Several mutations in many different proteins are associated with expression of hypertension, including abnormalities in the epithelial sodium channel (ENaC) found in absorptive organs (i.e., distal colon, distal tubule of the nephron). Some of these mutations result in structural and/or functional alterations in ENaC-mediated Na+ entry in epithelia responsible for fluid and electrolyte balance and are associated with expression of hypertension. Studies support the notion that there is a link between ENaC and hypertension of both the monogenic (single gene mutation) and primary or essential type (a multifactorial disease). Alterations of other aspects of the environment of absorptive cells (e.g., hyperinsulinemia, hyperaldosteronemia, high plasma cortisol, high plasma Na+) have also been shown to elicit hyperabsorption of Na+ via ENaC and therefore could contribute significantly to expression of hypertension in people with intermediate phenotypes. This article describes an initial study in which the effects of an environmental factor, extracellular levels of insulin, on ENaC were examined in a normal kidney cell model. Electrophysiologic techniques revealed that ENaC density rapidly increased in response to addition of insulin to the basolateral bath. This autoregulatory recruitment of Na+ total channel density masked a slight decrease in open channel probability. Insulin's effect on ENaC function and implications on fluid and electrolyte balance and expression of primary hypertension is discussed.
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PMID:Insulin increases sodium (Na+) channel density in A6 epithelia: implications for expression of hypertension. 1122 93

Hypertension is a major risk factor for heart attacks, stroke, and kidney failure. It is estimated to cause as many as 25% of all deaths in the United States, particularly for African Americans, in whom the disease is both more common and more severe. Essential hypertension is a multifactorial disorder influenced by both genetic and environmental factors. Physiological studies have shown that the kidneys play an important role in the maintenance of sodium balance, extracellular fluid volume, and long-term control of blood pressure. The sodium transporters in the kidney affect the amount of sodium and water reabsorption in the nephron and thus control extracellular fluid volume and blood pressure. Of the renal sodium transporters, the amiloride-sensitive epithelial sodium channels (ENaC), which are responsible for the rate-limiting step of sodium reabsorption in the distal nephron, are therefore important candidates in the development of hypertension. Moreover, mutations in this channel have been shown to cause a rare form of heritable hypertension (Liddle's syndrome), and genetic linkage studies show that the beta- and gamma-subunits are linked to systolic blood pressure. Several polymorphisms have been identified in the beta- and gamma-subunits of this channel, of which the beta-T594M variant is of particular interest. This variant is found in individuals of African American descent and not in Caucasians and may be associated with hypertension in some populations of African descent. Lymphocytes from individuals with this variant channel show an increased sodium conductance in response to cAMP in vitro. Studying the polymorphic variants in the various subunits of ENaC may further our understanding of the mechanisms that underlie sodium balance in mammals. These variants will provide an avenue to identify molecular targets for new diagnostic and therapeutic tools in the clinical treatment of hypertension.
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PMID:Epithelial sodium channels and hypertension. 1125 50

It remains to be defined whether molecular variants of the genes underlying Mendelian forms of hypertension play some etiological role in essential hypertension. To pursue this issue, we focused on the following three genes: the epithelial sodium channel (ENaC), 11beta-hydroxysteroid dehydrogenase type 2, and mineralocorticoid receptor genes. Five sequence variations of these genes, which were either previously reported to show significant association with hypertension or identified as "mild" molecular variants, were chosen for our study. Each variation was screened in 247 severe hypertensive patients with early onset (<45 years) and any detectable variations were subsequently characterized in 291 older normotensive subjects (>60 years) for the case-control comparison. We also investigated the significance of association between the tested variants and biochemical parameters reflecting sodium-water homeostasis, such as plasma aldosterone concentration (PAC) and renin activity (PRA). Only the T663A variant (alpha-subunit of ENaC) turned out to be polymorphic in the Japanese population. In disagreement with positive associations previously reported in white and black subjects, we observed no significant association between T663A and hypertension, while allele frequencies of A663 were higher in Japanese (58-64%) compared with a reported prevalence of 29% in whites and 15% in blacks. T663A showed a borderline association (p=0.02) with the PAC/PRA ratio but not with PAC or PRA in the multivariate analysis. Our data did not support the association between Mendelian disease gene variants and essential hypertension in the Japanese. However, the present study did not definitively resolve this issue and further investigation is certainly warranted.
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PMID:Evaluation of selected polymorphisms of the Mendelian hypertensive disease genes in the Japanese population. 1167 45


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