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)

We recently found in a white population that the genes encoding angiotensin-converting enzyme (ACE, I/D polymorphism), alpha-adducin (Gly460Trp), and aldosterone synthase (-344C/T) jointly influence renal function. We therefore investigated in a Chinese population the associations between the serum concentrations of creatinine and uric acid and these three genetic polymorphisms. We genotyped 471 ethnic Han Chinese subjects from 125 nuclear families recruited in northern China via random population sampling (75%) and at specialized hypertension clinics (25%). We performed population-based and family-based association analyses using generalized estimating equations (GEE) and quantitative transmission disequilibrium test (QTDT), respectively, while controlling for covariables. The participants were 39.7 years old and included 235 women (49.9%). The blood pressure measured at the subjects' homes averaged 126/80 mmHg. Mean values were 71 micromol/l for serum creatinine, 111 ml min(-1) 1.73 m(-2) for calculated creatinine clearance, and 236 micromol/l for serum uric acid. With adjustment for covariables, GEE analyses of single genes demonstrated that serum uric acid, but not serum creatinine, was positively associated with the ACE D allele. Serum uric acid concentrations were 15.8 micromol/l (95% confidence interval 3.3-28.2) and 25.7 micromol/l (11.1-40.2) higher in DD homozygotes than in ID and II subjects, respectively. Further GEE analyses of the three genes combined showed that the association between serum uric acid and the ACE polymorphism was confined to carriers of the alpha-adducin Gly and/or aldosterone synthase C alleles. Sensitivity analyses in parents and offspring separately as well as QTDT analyses were confirmatory. Among 114 informative offspring carrying the alpha-adducin Gly allele serum uric acid was significantly and positively associated with the transmission of the ACE D allele (beta=20.7 micromol/l). In conclusion, the present study extends our previous findings on the combined effects of the three candidate genes and supports the concept that these genetic polymorphisms jointly influence renal function.
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PMID:Renal function in relation to three candidate genes in a Chinese population. 1537 62

Increased sodium-lithium countertransport activity (SLC) associates with hypertension and is highly heritable, yet the underlying genes remain unknown. SLC, measured on 1113 and remeasured 2-3 years later on 675 adult members of 48 Utah pedigrees, was tested for candidate gene association, major locus inheritance, and linkage to genome scan markers using a bivariate model with genotype-specific effects of age, body mass index (BMI), and triglycerides level (TG). No effect of the alpha-adducin Gly460Trp polymorphism on SLC was found. In contrast, SLC increased with age in carriers of apolipoproteinE varepsilon2 (85 individuals; 8.7% of the sample) and decreased in noncarriers. Model-fitting analyses inferred two additional loci with genotype-specific responses to BMI and TG. Using the inferred model, lod scores >2 were obtained for D3S3038, D11S4464, and D10S677 for the BMI-responsive locus, and for D8S1048 for the TG-responsive locus.
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PMID:Model-fitting and linkage analysis of sodium-lithium countertransport. 1538 25

Arterial hypertension is one of the major cardiovascular risk factors in Western countries. Besides some well established, but rather rare forms of secondary hypertension, essential hypertension is the most common diagnosis. The hereditary nature of this disease has been well established in many familial studies. The quantitative contribution of genetic factors to blood pressure variance is estimated to be about 30%, however, the genetic background of essential hypertension is complex and currently not fully understood. Besides few monogenetic forms of Mendelian transmitted hypertension, current efforts are usually directed at the identification of single contributing genetic factors. This review is thought to highlight current strategies towards a better understanding of the genetic background of essential hypertension with particular respect to genetic variants of the renin-angiotensin system, of signaling pathways such as heterotrimeric G-proteins and alpha-adducin. Moreover, genetic association studies often fail to replicate findings from previous studies. This may be in part due to the polygenetic nature of the disease. Another potential reason may be the diversity of the investigated populations. The current results of genetic analyses of essential hypertension highlight, thus, the need for a more differentiated approach to the understanding of complex, polygenetic traits implementing gene-gene-, and gene-environment interactions or distinguished functional testing of thoroughly phenotyped cohorts under standardised environmental conditions.
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PMID:Genetics of human arterial hypertension. 1546 11

Alpha-adducin polymorphism in humans is associated with abnormal renal sodium handling and high blood pressure. The mechanisms by which mutations in adducin affect the renal set point for sodium excretion are not known. Decreases in Na+,K+-ATPase activity attributable to endocytosis of active units in renal tubule cells by dopamine regulates sodium excretion during high-salt diet. Milan rats carrying the hypertensive adducin phenotype have a higher renal tubule Na+,K+-ATPase activity, and their Na+,K+-ATPase molecules do not undergo endocytosis in response to dopamine as do those of the normotensive strain. Dopamine fails to promote the interaction between adaptins and the Na+,K+-ATPase because of adaptin-mu2 subunit hyperphosphorylation. Expression of the hypertensive rat or human variant of adducin into normal renal epithelial cells recreates the hypertensive phenotype with higher Na+,K+-ATPase activity, mu2-subunit hyperphosphorylation, and impaired Na+,K+-ATPase endocytosis. Thus, increased renal Na+,K+-ATPase activity and altered sodium reabsorption in certain forms of hypertension could be attributed to a mutant form of adducin that impairs the dynamic regulation of renal Na+,K+-ATPase endocytosis in response to natriuretic signals.
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PMID:Hypertension-linked mutation in the adducin alpha-subunit leads to higher AP2-mu2 phosphorylation and impaired Na+,K+-ATPase trafficking in response to GPCR signals and intracellular sodium. 1552 69

Previous studies have suggested that the Gly460Trp polymorphism of the alpha-adducin gene (ADD-1) is associated with salt sensitivity and primary hypertension. The results of linkage or association studies of ADD-1 of different populations are controversial. This study investigated the relationship between the Gly460Trp polymorphism of ADD-1 and essential hypertension in a Korean population. The subjects (n=903) were participants in a population-based study in Jangseong County, Korea. The Gly460Trp polymorphism of ADD-1 was determined using a polymerase chain reaction method. The frequency of the 460Trp allele was 59.4% in normotensives and 61.1% in hypertensives (p=0.523). The frequencies of the genotypes did not differ significantly between the hypertensive and normotensive groups (16.3% Gly/Gly, 45.8% Gly/Trp, and 38.0% Trp/Trp in normotensives; 16.2% Gly/Gly, 45.8% Gly/Trp, and 38.0% Trp/Trp in hypertensives; p=0.928). After adjusting for other risk factors, Gly/Trp and Trp/Trp were not associated with hypertension (OR 1.00, 95% CI 0.65-1.53, Gly/Trp vs. Gly/Gly; OR 1.22, 95% CI 0.79-1.90, Trp/Trp vs. Gly/Gly). These findings suggest that the Gly460Trp polymorphism of ADD-1 is not associated with hypertension.
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PMID:Alpha-adducin Gly460Trp polymorphism and essential hypertension in Korea. 1560 90

Genetic loci influencing the long-term levels and trends of blood pressure over time were investigated using 775 white siblings, ages 13 to 43 years, enrolled in the Bogalusa Heart Study, and 357 microsatellite markers on the 22 autosomal chromosomes. Subjects had been examined serially 2 to 12 times with 4365 serial observations over an average of 22 years from childhood to adulthood. Total and incremental area under the curve was calculated based on a cubic growth curve and used as long-term levels and trends, respectively. After adjusting for age, sex, and body mass index, heritability estimates of total area were 0.66 for systolic and 0.68 for diastolic blood pressure. Heritability of incremental area was 0.38 for systolic and 0.46 for diastolic blood pressure. Significant linkage to the total area of diastolic blood pressure (peak logarithm of odds [LOD]=3.9 at 73 cM) was observed on chromosome 2, with a region spanning from 44 cM to 103 cM showing supporting linkage evidence of LOD >3.0. In addition, suggestive linkage for total area of systolic (LOD=1.6 at 182 cM) and diastolic blood pressure (LOD=2.0 at 36 cM) on chromosome 4 and diastolic blood pressure incremental area (LOD=2.2 at 28 cM) on chromosome 18 was noted. Several hypertension candidate genes such as alpha-adducin, beta-adducin, sodium bicarbonate co-transporter, and G protein-coupled receptor kinase 4 are located in these regions. Linkage evidence found in this community-based study indicates that regions on these chromosomes harbor genetic loci that affect the propensity for development of hypertension from childhood.
Hypertension 2005 May
PMID:Autosomal genome scan for loci linked to blood pressure levels and trends since childhood: the Bogalusa Heart Study. 1580 62

Hypertension is the most common chronic disease in the Western world, and while there are many drug classes from which to choose therapy, only 34% of North Americans currently have their blood pressure controlled. The potential clinical utility of pharmacogenomics in helping to guide antihypertensive drug therapy selection is described. The hypertension pharmacogenetics literature is reviewed, which highlights that only a small fraction of the genes that likely contribute to antihypertensive response have been studied to date. The genes for alpha-adducin (diuretic response), the beta1-adrenergic receptor (beta-blocker response) and angiotensinogen (response to multiple drug classes) are among the genes with the most compelling data (based on replication) as pharmacogenetic candidates. Potential limitations of current studies are also discussed. These include reliance on clinic blood pressure, which is probably a suboptimal response phenotype, and the relatively small sample sizes of most studies to date. Also discussed is the relatively simplistic genetic approach that has been taken, which has focused largely on a single gene or single nucleotide polymorphism within a gene. Multiple ways to overcome these potential limitations are described. Hypertension pharmacogenomics holds tremendous potential for providing a mechanism by which management of hypertensive patients might be improved, and future studies should help move this field towards its clinical potential.
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PMID:Hypertension pharmacogenomics: current status and future directions. 1597 18

Preliminary evidence from 1 case-control study suggested that in hypertensive patients, the alpha-adducin 460Trp allele might be associated with a 2-fold higher risk of coronary heart disease. In a prospective population study, we investigated whether the alpha-adducin Gly460Trp polymorphism predicted mortality and morbidity. From August 1985 until July 2003, we randomly recruited 2235 Belgian residents. We obtained information on vital status (until July 1, 2004) and the incidence of events via registries and repeat examinations (median 3). In Cox regression, before and after adjustment for other risk factors, we found strong interaction between systolic blood pressure at baseline, analyzed as a continuous variable, and the alpha-adducin polymorphism in relation to total (P=0.01) and cardiovascular mortality (P=0.007) and all cardiovascular (P=0.003), cardiac (P=0.001), and coronary events (P=0.03). The hazard ratio for total mortality associated with the Trp allele relative to GlyGly homozygosity was 2.30 (95% confidence interval, 1.12 to 4.72; P=0.02) in patients with stage-2 systolic hypertension (> or =160 mm Hg) and 0.88 (0.61 to 1.26; P=0.48) in the other participants. For all cardiovascular complications, these estimates were 2.94 (1.28 to 6.74; P=0.01) and 0.83 (0.58 to 1.20; P=0.32), respectively. For all cardiovascular events, the positive predictive value and the attributable risk associated with the Trp allele in patients with stage-2 systolic hypertension were 76.9% and 44.3%, respectively. In conclusion, the alpha-adducin Gly460Trp polymorphism, in combination with systolic blood pressure, is a strong predictor of cardiovascular mortality and morbidity.
Hypertension 2005 Sep
PMID:Cardiovascular risk in relation to alpha-adducin Gly460Trp polymorphism and systolic pressure: a prospective population study. 1604 64

Effective blood pressure lowering is essential for prevention of complications of arterial hypertension. Most current guidelines indicate diuretics, beta-blockers, angiotensin converting enzyme inhibitors, calcium channel blockers and angiotensin receptor blockers as main antihypertensive drugs. Genetic polymorphisms underlie pathophysiology of diseases and can affect efficacy of therapy. Method of investigation of pharmacogenetic interrelationships is based on analysis of genes encoding enzymes responsible for metabolism and transport of drugs as well as genes encoding main targets of drug action (receptors). Those polymorphic genes that encode elements of the system of metabolism, adsorption, transport, elimination of drugs, and main receptor systems are considered to be main gene-candidates for pharmacogenetic studies. Some drugs have well known genotypes determining efficacy of therapy as for instance alpha-adducin gene for diuretics. Data on other classes of drugs (e.g. calcium channel blockers) are scanty. Existing information on pharmacogenetic properties of antihypertensive drugs is presented in this review.
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PMID:[Individual sensitivity to antihypertensive drugs: genetic aspects]. 1609 64

Adducin is a heterodimeric cytoskeleton protein consisting of an alpha-subunit and either a beta- or gamma-subunit. In rats and humans, mutation of the alpha-adducin subunit leads to the stimulation of the sodium (Na(+)), potassium (K(+))-adenosine triphosphate (ATP)-ase activity in renal tubular cells, increased renal Na(+) reabsorption, and, subsequently, hypertension. Ouabain is a hormone that is released by the hypothalamus and, possibly, the adrenal glands. In renal tubular cells it modulates Na(+)/K(+)-ATPase activity and regulates natriuresis. Plasma ouabain levels increase with the number of copies of the mutated alpha-adducin allele. Rostafuroxin is a digitoxygenin derivative that selectively displaces ouabain from the Na(+)/K(+)-ATPase receptor and lowers blood pressure in rats and humans. In this short editorial review, we summarize the recent experimental, clinical and epidemiological evidence that contributed to our understanding of the pathogenetic mechanisms that lead to hypertension associated with the alpha-adducin Gly460Trp polymorphism and its interaction with ouabain. We propose that a pharmacogenomic approach, as applied in an ongoing Phase II dosage study of rostafuroxin, will be a critical step in moving the adducin hypothesis from experimental and observational studies to clinical application.
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PMID:Adducin and hypertension. 1620 43


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