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

This review summarizes the current status of our knowledge about the role of pharmacogenetic variation in response to diuretics and suggests future research topics for the field. Genes with a role in the pharmacokinetics of most diuretics are renal drug transporters, especially OAT1, OAT3 and OCT2 (genes SLC22A6, SLC22A8 and SLC22A2) whereas variants in carbonic anhydrase (CA), cytochrome P450 enzymes and sulfotransferases are relevant only for specific substances. Genes on the pharmacodynamic side include the primary targets of thiazide, loop, K(+)-sparing and aldosterone antagonistic diuretics: NCC, NKCC2, ENaC and the mineralocorticoid receptor (genes SLC12A3, SLC12A1, SCNN1A, B, G and NR3C2). Rare variants of these proteins cause Gitelman's syndrome, Bartter's syndrome, Liddle's syndrome or pregnancy-induced hypertension. Polymorphisms in these and in associated proteins such as GNB3, alpha-adducin and angiotensin-converting enzyme (ACE) seem to be clinically relevant. In conclusion, first knowledge has evolved that efficacy of diuretic drugs may be determined by genetic polymorphisms in genes determining pharmacokinetics and pharmacodynamics of this drug class. In the future, the selection of a diuretic drug or the dosing schedules may be individually chosen based on pharmacogenetic parameters, however, many questions remain to be answered before this fantasy becomes reality.
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PMID:Pharmacogenomics of diuretic drugs: data on rare monogenic disorders and on polymorphisms and requirements for further research. 1459 36

The response of blood pressure to thiazide diuretics (TZDs) differs among individuals. The prediction of the antihypertensive effect of TZDs is important for realizing individualized therapy in the management of hypertension. The aim of this study was to identify the single nucleotide polymorphisms (SNPs) susceptible to the antihypertensive effect of TZDs, particularly focusing on genes related to water-electrolyte absorption in the kidney. Seventy-six outpatients (mean age, 65.4+/-9.0 years) with essential hypertension (EHT) taking TZDs were retrospectively assessed. We defined as responders (R) those whose mean blood pressure was lowered by more than 5 mmHg after the use of TZDs. Forty-eight SNPs in 17 genes (ADD1, GNB3, TSC [SLC12A3], MLR [NR3C2], NCX1 [SLC8A1], WNK1, WNK4, AGT, ACE, AT1 [AGTR1], CYP11B2, ADRB1, ADRB2, ADRB3, ADRA1A, ADRA1B, ADRA2A) were genotyped in the 76 patients. The SNPs in TSC, MLR, NCX1, WNK1, and WNK4 were identified by direct sequencing and those with minor frequencies of greater than 5% were genotyped in this study. The comparison of polymorphism prevalence between R and non-responders (NR) showed significant differences in TSC C1784T (C allele vs. T allele, odds ratio (OR)=3.81, p =0.016, confidence interval (CI): 1.25-11.63) and ADRB3 T727C (Trp64Arg) (T allele vs. C allele, OR=4.59, p =0.005, CI: 1.54-13.68). The blood pressure (BP) in patients homozygous for the major alleles of both TSC C1784T and ADRB3 T727C were significantly reduced by TZD treatment; however, the BP in those homozygous for the minor allele and heterozygous (TSC C1784T: TT+CT; ADRB3 T727C: CC+CT) for both SNPs were not significantly changed after TZD treatment. Both newly detected TSC C1784T and ADRB3 T727C are gene polymorphisms susceptible to the antihypertensive effect of TZDs in patients with EHT. Thus, the prediction of BP reduction by TZDs may be possible by evaluating these two SNPs.
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PMID:The thiazide-sensitive Na(+)-Cl(-) cotransporter gene, C1784T, and adrenergic receptor-beta3 gene, T727C, may be gene polymorphisms susceptible to the antihypertensive effect of thiazide diuretics. 1582 64

A gain-of-function mutation resulting in the S810L amino acid substitution in the hormone-binding domain of the mineralocorticoid receptor (MR, locus symbol NR3C2) is responsible for early-onset hypertension that is exacerbated in pregnancy. The objective of this study was to test whether other types of missense mutations in the hormone-binding domain could be implicated in hypertension in Japanese. Here, we screened 942 Japanese patients with hypertension for the S810L mutation in exon 6 in the MR. We did not identify the S810L mutation in our hypertensive population, indicating that S810L does not play a major role in the etiology of essential hypertension in Japanese. However, we identified a novel missense mutation, F826Y, in three patients in a heterozygous state, in addition to four single nucleotide polymorphisms, including one synonymous mutation (L809L). The F826Y mutation is present in the MR hormone-binding domain and might affect the ligand affinity. The F826Y mutation was also identified in 13 individuals (5 hypertensives and 8 normotensives) in a Japanese general population (n=3,655). The allele frequency was 0.00178. The frequencies of the F826Y mutation in the hypertensive population (3/942) and in the hypertensive group (5/ 1,480) and the normotensive group (8/2,175) in the general population were not significantly different, suggesting that this mutation does not greatly affect hypertension. Although it is unclear at present whether or not the F826Y mutation makes a substantial contribution to the mineralocorticoid receptor activity, this missense mutation may contribute, to some extent, to clinical phenotypes through its effects on MR.
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PMID:A novel missense mutation, F826Y, in the mineralocorticoid receptor gene in Japanese hypertensives: its implications for clinical phenotypes. 1641 42

Aldosterone plays a key role in electrolyte balance and blood pressure regulation. Type 1 pseudohypoaldosteronism (PHA1) is a primary form of mineralocorticoid resistance characterized in the newborn by salt wasting, hyperkalemia, and failure to thrive. Inactivating mutations of the mineralocorticoid receptor (MR; NR3C2) are responsible for autosomal dominant and some sporadic cases of PHA1. The question as to whether other genes may be involved in the disease is of major importance because of the potential life-threatening character of the disease, the potential cardiovascular effects of compensatory aldosterone excess, and the role of the mineralocorticoid system in human hypertension. We present the first comprehensive study seeking nucleotide substitutions in coding regions, intron-exon junctions, and untranslated exons, as well as for large deletions. A total of 22 MR gene abnormalities were found in 33 patients. We demonstrate that MR mutations are extremely frequent in PHA1 patients classified according to aldosterone and potassium levels and give indications for accurate clinical and biological investigation. In our study the possibility of a genocopy exists in three PHA1 kindreds. The other patients without MR mutations might have different diseases resembling to PHA1 in the neonatal period, which could be identified by extensive clinical and functional exploration.
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PMID:Mineralocorticoid receptor mutations are the principal cause of renal type 1 pseudohypoaldosteronism. 1697 28

The genes responsible for several monogenic hypertensive and hypotensive disorders have been identified. Our aim was to evaluate whether common variants in these genes affect blood pressure in the general population. We studied 2037 adults from 520 nuclear families characterized for 24-hour ambulatory blood pressure and related cardiovascular traits. We genotyped 298 tagging and putative functional single nucleotide polymorphisms, achieving a median coverage of 82.4% across 11 candidate loci. Five polymorphisms in the KCNJ1 gene coding for the potassium channel, ROMK, showed associations with mean 24-hour systolic or diastolic blood pressure. The strongest association was with an intronic polymorphism, rs2846679, where the minor allele (frequency 16%) was associated with a -1.58 (95% CI -2.47 to -0.69) mm Hg change in mean 24-hour systolic blood pressure, after accounting for age, sex, and familial correlations (P=0.00048). Polymorphisms in the gene were also associated with clinic blood pressure and left ventricular mass as assessed by ECG Sokolow-Lyon voltage (P=0.0081 for rs675759). Associations with mean 24-hour systolic or diastolic blood pressure were also observed for variants in CASR, NR3C2, SCNN1B, and SCNN1G. The findings show that common variants in genes responsible for some Mendelian disorders of hypertension and hypotension affect blood pressure in the general population. Notably, variants in KCNJ1, which causes Bartter syndrome type 2, were strongly associated, potentially providing a novel target for intervention.
Hypertension 2008 Jun
PMID:Common variants in genes underlying monogenic hypertension and hypotension and blood pressure in the general population. 1844 36

MicroRNAs (miRNAs) comprise a post-transcriptional layer of gene regulation shown to be involved in diverse physiological processes. We aimed to study whether regulatory networks that determine susceptibility to hypertension may involve a miRNA component. Screening of loci, involved in renal water-salt balance regulation, highlighted the mineralocorticoid receptor gene NR3C2 as a potential target for several miRNAs. A luciferase assay demonstrated that miR-124 and miR-135a suppress NR3C2 3'UTR reporter construct activity 1.5- and 2.2-fold, respectively. As the tested miRNAs did not reduce the levels of target mRNA, we suggest that the binding of miR-124 and miR-135a to NR3C2 3'UTR contributes to the translational, not transcriptional regulation of the gene. Co-expression of two different miRNAs did not increase the repression of the reporter gene, indicating no additive or synergistic effects between the tested miRNAs. Our results demonstrate that by repressing the mineralocorticoid receptor gene NR3C2, miR-124 and miR-135a could participate in the regulation of renin-angiotensin-aldosterone system and thereby might be involved in blood pressure regulation.
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PMID:MicroRNAs miR-124 and miR-135a are potential regulators of the mineralocorticoid receptor gene (NR3C2) expression. 1994 75

AIMS. Blood pressure control is influenced by various genetic and environmental factors, and genetic susceptibility is important in the development of essential hypertension. Because the renin-angiotensin-aldosterone system (RAAS) has a key role in vasoconstriction, vasodilation, and sodium and electrolyte balance, it is central in blood pressure control and so is an appropriate target in hypertension treatments. The present study assessed the association of RAAS-related genes with blood pressure and hypertension in a Korean population. Single nucleotide polymorphisms (SNPs, n = 114) in nine RAAS-related genes (AGT, REN, ACE, ACE2, AGTR1, CYP11B2, NR3C2, MAS1, and CMA1) were assessed for their correlation with blood pressure and hypertension using genotype data of 8842 individuals from the Korea Association Resource subject pool. MAJOR FINDINGS. Linear regression analysis revealed a statistically significant association with blood pressure of 10 SNPs in six genes (ACE, ACE2, CYP11B2, NR3C2, MAS1, and CMA1). An additional hypertension case-control study identified 10 SNPs in NR3C2 and ACE that were linked to hypertension. PRINCIPAL CONCLUSION. Three SNPs (rs11737660, rs6810951, and rs10519963) in NR3C2 correlate with both blood pressure and hypertension. Genetic polymorphisms in RAAS-related genes appear to be associated with hypertension in a Korean population.
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PMID:Association between renin-angiotensin-aldosterone system-related genes and blood pressure in a Korean population. 2134 26

There is evidence that uncontrolled arterial hypertension (AHT) in patients with metabolic syndrome (MS) increases cardiovascular risks. The renin-angiotensin-aldosterone system (RAAS) and its polymorphisms apparently confer a genetic risk for uncontrolled AHT. This study aims to investigate the influence of RAAS polymorphisms on AHT control in patients diagnosed with MS. This is a two-stage population-based nested case-control pilot study (n=1514). We differentiated between MS-diagnosed patients and non-MS patients (ATP-III criteria) and selected those individuals diagnosed with AHT from each group (n=161 and n=156, respectively). Those who successfully controlled their AHT (controls) and those who did not were compared. In the MS population, the C/G and G/G genotypes of single-nucleotide polymorphism rs1040288 (NR3C2) and A/G and G/G of rs11099680 (NR3C2) were associated with uncontrolled AHT (odds ratio (OR)=2.94 (1.34-6.47) and OR=2.54 (1.09-5.93), respectively). According to Akaike's information criteria, the best adjusted model included gender and age as confounding variables (adjusted OR (ORa)=2.91 (1.31-6.46) and ORa=2.67 (1.13-6.31), respectively). Regarding rs1040288, an ORa of 4.03 (1.44-11.26) was obtained for the saturated model (adjusted for gender, age, waist-to-hip ratio, body mass index, biochemical profile, renal damage, smoking habit and anti-AHT treatment). Yet, when the same analysis was performed on the non-MS population, no association was found between rs11099680 and the failure to control AHT. The results reveal a possible association between the rs11099680 RAAS polymorphism and uncontrolled AHT in MS-diagnosed patients. rs1040288 appears to be associated with uncontrolled blood pressure regardless of MS profile.
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PMID:Inefficient arterial hypertension control in patients with metabolic syndrome and its link to renin-angiotensin-aldosterone system polymorphisms. 2147 72

Blood pressure (BP) is a dynamic phenotype that varies rapidly to adjust to changing environmental conditions. Standing upright is a recent evolutionary trait, and genetic factors that influence postural adaptations may contribute to BP variability. We studied the effect of posture on the genetics of BP and intermediate BP phenotypes. We included 384 sib-pairs in 64 sib-ships from families ascertained by early-onset hypertension and dyslipidemia. Blood pressure, three hemodynamic and seven neuroendocrine intermediate BP phenotypes were measured with subjects lying supine and standing upright. The effect of posture on estimates of heritability and genetic covariance was investigated in full pedigrees. Linkage was conducted on 196 candidate genes by sib-pair analyses, and empirical estimates of significance were obtained. A permutation algorithm was implemented to study the postural effect on linkage. ADRA1A, APO, CAST, CORIN, CRHR1, EDNRB, FGF2, GC, GJA1, KCNB2, MMP3, NPY, NR3C2, PLN, TGFBR2, TNFRSF6, and TRHR showed evidence of linkage with any phenotype in the supine position and not upon standing, whereas AKR1B1, CD36, EDNRA, F5, MMP9, PKD2, PON1, PPARG, PPARGC1A, PRKCA, and RET were specifically linked to standing phenotypes. Genetic profiling was undertaken to show genetic interactions among intermediate BP phenotypes and genes specific to each posture. When investigators perform genetic studies exclusively on a single posture, important genetic components of BP are missed. Supine and standing BPs have distinct genetic signatures. Standardized maneuvers influence the results of genetic investigations into BP, thus reflecting its dynamic regulation.
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PMID:Dynamic genetic linkage of intermediate blood pressure phenotypes during postural adaptations in a founder population. 2326 1

Pseudohypoaldosteronism (PHA) is a rare syndrome of mineralocorticoid resistance. PHA type 1 (PHA1) can be divided into two different forms, showing either a systemic or a renal form of mineralocorticoid resistance. The first is caused by mutations of the genes coding the epithelial sodium channel, the latter is caused by mutations in the mineralocorticoid receptor coding gene NR3C2. The clinical manifestation of systemic PHA1 is overt dehydration and hyponatremia due to systemic salt loss and severe hyperkalemia. The leading clinical sign of the less severe renal PHA1 is insufficient weight gain due to chronic dehydration. Hyperkalemia is generally mild. The patients manifest clinical signs mainly in early infancy. In both entities, plasma renin and aldosterone concentrations are highly elevated, reflecting a resistance of the kidney and other tissues to mineralocorticoids. PHA2 is characterized by hyperkalemia and hypertension. It has been described by Gordon's group as a syndrome with highly variable plasma aldosterone concentrations, suppressed plasma renin activity, various degrees of hyperchloremia and metabolic acidosis. PHA3 comprises transient and secondary forms of salt-losing states caused by various pathologies. Urinary tract infections and obstructive uropathies are the most frequent cause. Contrary to PHA1 and PHA2, the glomerular filtration rate is decreased in PHA3.
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PMID:Pseudohypoaldosteronism. 2339 97


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