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)

Human chromosome 17q has been implicated to contain a gene that influences hypertension susceptibility. This region contains the WNK4 gene that causes the mendelian disorder pseudohypoaldosteronism type II, characterized by high potassium levels and hypertension. The goal of this study was to identify genetic variants in all exons of WNK4 in hypertensive individuals and to examine the association of these variants with essential hypertension. Single-nucleotide polymorphims (SNPs) were identified by sequencing the entire coding region in 32 whites and 32 African Americans with hypertension. A single SNP in whites and 8 SNPs in African Americans were genotyped in a larger cohort of whites (165 hypertensives; 91 normotensives) and African Americans (120 hypertensives; 98 normotensives). The frequency of the rare allele differed significantly between hypertensive whites (13.0%) and normotensive whites (7.1%, P=0.040) for the single intronic SNP (bp 1 156 666). This difference remained significant after adjusting for body mass index and sex (P=0.035). Genotypic frequencies differed significantly between hypertensive and normotensive individuals when a dominant model either with (P=0.027) or without (P=0.028) covariate adjustment was assumed. The odds ratio for hypertension was 2.28 for AA or AG individuals vs those with the GG genotype (95% confidence interval, 1.09 to 4.75). No significant differences in allelic or genotypic frequencies were observed in African Americans for any SNPs. The finding in whites is consistent with the hypothesis that polymorphisms in WNK4 influence the risk of hypertension. However, because the associated SNP does not appear to be a functional variant and the limitations of case/control association studies, confirmation of these results in additional cohorts is warranted.
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PMID:Genetic variants of WNK4 in whites and African Americans with hypertension. 1271 38

In a study of the genetic basis of essential hypertension (HT), we tested four variants in three candidate genes not previously investigated in HT. These encoded the endothelin receptor type A (EDNRA), which transduces most of the vasoconstrictive properties of endothelin-1, protein kinase lysine deficient 4 (WNK4) whose gene resides in a HT linkage region on chromosome 17, and FK506-binding protein 1B (FKBP1B), which can reduce blood pressure by increasing nitric oxide. The variants were: for EDNRA, a G-->A in the 5'-UTR and C-->T in exon 8; for WNK4, a tetranucleotide repeat in intron 10; and for FKBP1B, a T-->C in exon 4. Subjects were Anglo-Celtic white Australians and included 155 HTs with two HT parents and 245 normotensives (NTs) whose parents were both NT. For EDNRA, we found a weak association of the exon 8 variant with HT (p = 0.019) and association of the 5'-UTR variant with elevation in systolic and diastolic blood pressure (BP) (p = 0.038 and 0.0031, respectively). The WNK4 intron 10 variant and the FKP1B exon 4 variant showed no association with HT, but tracking with BP was seen for the latter (p = 0.015 and 0.0011 for systolic and diastolic BP, respectively). Our study thus suggests possible involvement of EDNRA in essential HT.
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PMID:Association of EDNRA, but not WNK4 or FKBP1B, polymorphisms with essential hypertension. 1461 68

Essential hypertension affects 1 billion people worldwide and its genetic basis is well established. For this review we surveyed the literature on the genetics of hypertension during the past 18 months and we now report the highlights. There has been publication of the two largest genome scans for blood pressure and new loci including significant linkage to chromosome 6q have been reported. The molecular basis of Gordon's syndrome has been partially unravelled with a dual function for WNK4 in ion transport regulation being discovered. There has also been progress in narrowing rodent quantitative trait loci using congenic approaches and several linkage peaks have now been demonstrated to have more than one loci. We also report some of the initial findings from pharmacogenetic studies.
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PMID:Genetics of essential hypertension. 1476 24

A polymorphism in intron 10 of the serine-threonine kinase with no lysine (K) 4 gene WNK4 (G-->A, base 1156666 on chromosome 17) has recently been associated with essential hypertension in a white American population. We have attempted to replicate this finding in a well characterized cohort of 184 unrelated hypertensive Australians of British extraction in which biological power was enhanced by them each having 2 hypertensive parents. Controls were 219 normotensive ethnically matched subjects whose parents were both normotensive. Genotyping was performed using the homogeneous MassEXTEND Assay. This showed a frequency of 0.10 for the minor allele in each group (P=0.88). Moreover, blood pressure, body mass index, sex, and plasma lipid levels were similar across genotypes. In conclusion, our study provides no support for an association of the intron 10 variant of WNK4 with essential hypertension in the Anglo-Australian population studied.
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PMID:WNK4 intron 10 polymorphism is not associated with hypertension. 1496 40

The deletion of thiazide-sensitive Na-Cl cotransporter ( TSC, SLC12A3) causes Gitelman's syndrome characterized by low blood pressure, while deletions of the WNK1 ( PRKWNK1) and WNK4 ( PRKWNK4) genes cause familial hypertension known as pseudohypoaldosteronism type II. Recent studies have revealed that cell surface expression of TSC is regulated by WNK1 and WNK4. We hypothesized that molecular variations in TSC, WNK1, and WNK4 could lead to an increased morbidity of hypertension. We identified 52, 35, and 21 polymorphisms in Japanese hypertensives by sequencing the entire coding regions of TSC, WNK1 and WNK4, respectively. Twenty-one representative polymorphisms were genotyped in 1,818 Japanese individuals (771 subjects with hypertension and 1,047 controls) randomly sampled in Suita city. The results indicated that the systolic blood pressure in men with the CT+TT genotype in WNK4 C14717T was 3.1 mmHg higher than those with the CC genotype ( p=0.042) after adjustment with confounding factors such as age, BMI, hyperlipidemia, diabetes mellitus, antihypertensive drug use, smoking, and drinking. Multivariate logistic regression analysis (with adjustment for the same parameters) in men revealed that the odds ratio for the presence of hypertension of the CT+TT genotype in C14717T to the CC genotype was 1.62 ( p=0.010, 95% confidence interval, 1.12-2.33). Association of TSC and WNK1 with hypertension was not observed. In conclusion, our study suggests the possible involvement of WNK4 in essential hypertension in a Japanese general population.
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PMID:Identification of 108 SNPs in TSC, WNK1, and WNK4 and their association with hypertension in a Japanese general population. 1530 83

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

The WNK kinases are a small group of serine/threonine kinases with unique catalytic domains that lack the lysine residue used in other kinases to co-ordinate ATP (hence, With No K [WNK]). Their closest homologues are found within the mitogen-activated protein kinase (MAPK) pathway suggesting a role in signalling. Two WNK isoforms, WNK1 and WNK4, have been identified as the disease genes for a rare monogenic hypertension syndrome (Gordon's syndrome or pseudohypoaldosteronism type 2 [PHA2]) implicating them in salt homeostasis by the kidney. This is supported by recent data showing widespread expression of WNK1 and WNK4 in mammalian transporting epithelia. Within the kidney, WNKs probably regulate the surface expression of several proteins involved in ion transport, including the sodium-chloride cotransporter (NCCT) and the potassium channel renal outer medullary potassium channel (ROMK), based on co-expression studies in Xenopus oocytes. WNKs, especially WNK4, have been suggested as candidate genes for essential hypertension itself, but evidence for this is lacking. Some of the effects of the WNKs are independent of their kinase function, suggesting that they are dependent on specific protein-protein interactions. It seems likely that the WNKs are part of much larger protein scaffolds in cells and have effects in cells beyond ion transport. However, because of their effect on expression of the NCCT they are attractive drug targets for the development of novel antihypertensive agents. These agents could potentially offer the efficacy of a thiazide diuretic, but without the metabolic side effects usually seen with this class of antihypertensive therapy.
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PMID:WNK kinases and the control of blood pressure. 1586 21

The pathogenesis of essential hypertension remains unknown, but thiazide diuretics are frequently recommended as first-line treatment. Recently, familial hyperkalemic hypertension (FHHt) was shown to result from activation of the thiazide-sensitive Na-Cl cotransporter (NCC) by mutations in WNK4, although the mechanism for this effect remains unknown. WNK kinases are unique members of the human kinome, intimately involved in maintaining electrolyte balance across cell membranes and epithelia. Previous work showed that WNK1, WNK4, and a kidney-specific isoform of WNK1 interact to regulate NCC activity, suggesting that WNK kinases form a signaling complex. Here, we report that WNK3, another member of the WNK kinase family expressed by distal tubule cells, interacts with WNK4 and WNK1 to regulate NCC in both human kidney cells and Xenopus oocytes, further supporting the WNK signaling complex hypothesis. We demonstrate that physiological regulation of NCC in oocytes results from antagonism between WNK3 and WNK4 and that FHHt-causing WNK4 mutations exert a dominant-negative effect on wild-type (WT) WNK4 to mimic a state of WNK3 excess. The results provide a mechanistic explanation for the divergent effects of WT and FHHt-mutant WNK4 on NCC activity, and for the dominant nature of FHHt in humans and genetically modified mice.
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PMID:The thiazide-sensitive Na-Cl cotransporter is regulated by a WNK kinase signaling complex. 1797 63

Two members of a recently discovered family of protein kinases are the cause of an inherited disease known as pseudohypoaldosteronism type II (PHAII). These patients exhibit arterial hypertension together with hyperkalemia and metabolic acidosis. This is a mirror image of Gitelman disease that is due to inactivating mutations of the SLC12A3 gene that encodes the thiazide-sensitive Na(+):Cl(-) cotransporter. The uncovered genes causing PHAII encode for serine/threonine kinases known as WNK1 and WNK4. Physiological and biochemical studies have revealed that WNK1 and WNK4 modulate the activity of several transport pathways of the aldosterone-sensitive distal nephron, thus increasing our understanding of how diverse renal ion transport proteins are coordinated to regulate normal blood pressure levels. Observations discussed in the present work place WNK1 and WNK4 as genes involved in the genesis of essential hypertension and as potential targets for the development of antihypertensive drugs.
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PMID:WNK kinases, renal ion transport and hypertension. 1854 46

Subtle genetic variants in ion-channel genes might be at the origin of less rare forms of hypertension in the general population. To test this hypothesis, we observed the role of several important polymorphisms (T1155547C at exon7, G1155942T at exon8, G1156666A at intron10, and C1163527T at intron14) of WNK4 (with-no-kinase) gene on the prevalence of essential hypertension in a Chinese minority ethnic group-the Uyghur population. We did not find a significantly different distribution of genotype and allele frequency of T1155547C, G1155942T, and G1156666A between hypertensives and controls, but we observed a significantly higher frequency of T allele in hypertensive subjects than controls (8.4% vs. 5.7%) (P = 0.02) of C1163527T polymorphism at intron14. Compared with the individuals with two C allele, individuals with at least one T allele show 55% of excess risk in developing hypertension (OR = 1.56, 95% CI:1.06-2.28). In a further analysis, we did not observe a significantly higher or lower odds ratio of haplotype frequency in the hypertensives than in the controls across haplotype encompassing G1155942T, G1156666A, and C1163527T. Thus, a positive association of C1163527T at intron 14 reveals that the WNK4 gene might be involved in the prevalence of essential hypertension in the Uyghur population. Further study should be conducted to observe the role of this gene on hypertension in other populations.
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PMID:WNK4 polymorphisms and essential hypertension in the Uyghur population. 1933 Jun 5


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