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: EC:3.4.15.1 (ACE)
18,300 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Essential hypertension affects approximately 20% of the adult population, and has a multifactorial origin arising from an interaction between susceptibility genes and environmental factors. The understanding of the molecular basis of essential hypertension may provide us with new and more specific pharmacological agents, and perhaps the ability to individualise treatment and maximise the reduction in risk of morbidity and mortality from cardiovascular disease. Hypertension due to single gene abnormalities is very rare; however, it follows a Mendelian model of inheritance and therefore can be identified successfully using family linkage studies. Since clear Mendelian models of inheritance cannot readily be assigned in essential hypertension as there may be variable penetrance of susceptibility genes, other studies with designs based on affected sibling pairs, family-based association studies and case-control studies have been performed. The renin-angiotensin system (RAS) plays an integral part in the control of blood pressure, and genetic polymorphisms within this system and their effect on the response to antihypertensive therapy are now being studied. Polymorphisms of the angiotensin converting enzyme (ACE) gene, although associated with left ventricular hypertrophy, do not appear to have a clear association with hypertension. Studies on the association of genotype with response to antihypertensive therapy are less consistent for genetic polymorphisms of the RAS. Although some of the results are positive, patient numbers have been small in the studies completed to date. Genetic polymorphisms of the adrenergic receptors have been associated with blood pressure variation in African-Americans, White Americans and African-Caribbeans. A beta 2-adrenoceptor polymorphisms exhibits agonist-mediated receptor downregulation which may lead to enhanced peripheral vasoconstriction. Therapeutic studies have not yet been completed on patients with this genotype. A further polymorphism of the alpha-adducin gene has been associated with essential hypertension. This may influence blood pressure response to sodium loading/depletion and response to long term treatment with a thiazide diuretic, but further studies are needed to clarify this. Antisense oligonucleotides targeted against genes of the RAS, e.g. angiotensinogen and the angiotensin type 1 receptor, are being modified to improve targeting and thereby reduce toxicity. However, gene therapy is unlikely to replace pharmacological therapy in the foreseeable future. The immediate goal should be to enhance our understanding of the genetic nature of essential hypertension based on the interaction of genetic makeup with the environment, with a view to individualising antihypertensive therapy.
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PMID:Genetics of hypertension. Therapeutic implications. 971 45

A Gly460Trp variant of the cytoskeletal protein alpha-adducin has recently been implicated in the etiology of essential hypertension (HT) in a study involving southern European whites. We attempted to replicate this finding in a well-characterized, extensively studied group of 112 white Australians with essential HT, with strong family history (two HT parents), early-onset, moderate to severe disease, and of British extraction. Controls were 196 normotensive (NT) white subjects whose parents were both NT older than age 50 years. A mismatch polymerase chain reaction method involving BanII was developed for genotyping. Frequency of the Trp460 allele was 0.23 in the HT and 0.24 in the NT groups (chi2 = 0.2, P = .7). No association was observed with blood pressure, body mass index, age, plasma renin, angiotensinogen, angiotensin converting enzyme, cholesterol, triglycerides, or HDL or LDL cholesterol. Our results therefore provide no support for a role for the alpha-adducin variant in hypertension, at least in our severely affected Anglo-white group with strong family history of HT.
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PMID:The Gly460Trp variant of alpha-adducin is not associated with hypertension in white Anglo-Australians. 1037 74

Recent developments in molecular biological techniques allowed us to examine the genetic risk factors responsible for essential hypertension. The candidate gene approach revealed that several gene polymorphisms increase the relative risk for hypertension. Most genetic studies, however, examined only young subjects but not elderly ones. To examine the importance of gene polymorphisms in elderly hypertension, we carried out a case-control study and compared the odds ratio for hypertension between young (< 60) and elderly (> or = 60) subjects. The participants of this study were recruited from the outpatients of Osaka University Medical School with informed consent. We examined the following polymorphisms as candidates: the angiotensinogen (AGT/M235T), angiotensin converting enzyme (ACE I/D), angiotensin II type 1 (AT1/A1166C) and type 2 (AT2/C3123A) receptors, alpha-adducin (adducin/Gly460Trp), methylenetetrahydrofolate reductase (MTHHR/C677T), and apolipoprotein (apoE/epsilon 4, apoE/T-491A). In young subjects, the AGT/T235 allele significantly increased the odds ratio for hypertension but not in elderly subjects. In young males, the AT2/A3123 allele was also associated with hypertension but not in females or in elderly subjects. Other associations between polymorphism and hypertension did not reach a significant level. To sum up, it was revealed that some polymorphisms increase the susceptibility for hypertension but others do not, which suggests that there is heterogeneity in the genetic involvement of polymorphism due to aging.
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PMID:[Genetic analysis of candidate gene polymorphisms in elderly hypertension]. 1055 62

This study focused on two genes that have previously been implicated in hypertension and may influence renal sodium handling, adducin, and angiotensin I-converting enzyme (ACE). We compared their polymorphic frequencies and interaction in patients with essential hypertension (n=128) and individually age- and gender-matched normotensive control subjects. The alpha-adducin G460W polymorphism was genotyped by DNA amplification and restriction digestion. The ACE I/D polymorphism was assayed by a triple-primer method, with a "nested" polymerase chain reaction primer situated completely within the insertion sequence of the I: allele. The distributions of genotypes and alleles for the two polymorphisms were not significantly different between the case and control populations, and the cross-classification of cases by alpha-adducin and ACE genotype gave a distribution similar to that of control subjects. We have previously reported that the distributions of genotypes for two linked polymorphisms in the aldosterone synthase gene (one in the steroidogenic factor-1 [SF-1] binding site and the other an intronic conversion [IC]) were significantly different between this cohort of essential hypertensives and matched control subjects. The cross-classification of cases by alpha-adducin and SF-1, alpha-adducin and IC, ACE and SF-1, and ACE and IC genotype gave a distribution similar to that of control subjects. Hence, no evidence was found to suggest an association between either the alpha-adducin G460W or the ACE I/D polymorphism and hypertension in a careful case-control study. Furthermore, the alpha-adducin G460W, ACE I/D, and aldosterone synthase SF-1 and IC polymorphisms do not appear to interact in our hypertensive population.
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PMID:alpha-adducin and angiotensin I-converting enzyme polymorphisms in essential hypertension. 1111 13

Different genetic polymorphisms influence cardiovascular disease. We recently discovered a relationship between the intima-media thickness of the muscular femoral artery, but not the elastic common carotid artery, and the combined ACE (ACE, I/D), alpha-adducin (Gly460Trp),and aldosterone synthase (AS, C-344T) gene polymorphisms. To investigate the relationship between these polymorphisms and functional properties of the carotid artery and femoral artery, a sample of 756 subjects enrolled in a population study were genotyped for the presence of the ACE D, alpha-adducin 460Trp, and aldosterone synthase -344T alleles. Vessel wall properties were assessed using a vessel wall movement detector system in combination with applanation tonometry. Statistical analysis allowed for confounders and interaction among genes. Cross-sectional compliance of the common carotid artery was negatively associated with the ACE D allele. ACE II versus ACE DD homozygotes differed, expressed as a percentage of the population mean (7.0%; 95% confidence interval [CI], 1.6% to 12.4%; P=0.02). In multigene analysis, ACE DD subjects also deviated significantly from the population mean for the distensibility coefficient of the common carotid artery when carrying the AS/T allele (-5.5%; 95% CI, -9.3% to -1.7%; P<0.01), without a change in cross-sectional compliance. ACE DD subjects, when homozygote for alpha-adducin Gly460, had a lower femoral cross-sectional compliance (-10.4%; 95% CI, -1.9% to -18.9%; P<0.03) and a lower distensibility (-9.7%; 95% CI, -2.1% to -17.3%; P<0.02) compared with the population mean. These data show that functional large artery properties are influenced by the ACE I/D polymorphism. Cross-sectional compliance and distensibility coefficients are influenced by the ACE I/D genotype, but this influence depends on the vascular territory and genetic background.
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PMID:Carotid and femoral artery stiffness in relation to three candidate genes in a white population. 1171 21

We recently found that femoral intima media thickness, as well as the incidence of hypertension, is influenced by genes encoding the angiotensin-converting enzyme (ACE; insertion/deletion [I/D]) polymorphism, alpha-adducin (Gly460Trp), and aldosterone synthase (-344C/T). By interfering with blood pressure or sodium homeostasis, these genetic polymorphisms also may change renal function. We therefore investigated serum creatinine level, calculated and measured creatinine clearances, and 24-hour urinary protein excretion in subjects previously genotyped for these three polymorphisms. The 1,454 participants drawn at random from the population (64.3% of those invited) were aged 43.4 years and included 744 women (51.2%). Blood pressure, measured by study nurses at subjects' homes, averaged 123/76 mm Hg. Mean values were 90 micromol/L for serum creatinine; 84 and 88 mL/min/1.73 m(2) for calculated and measured (n = 855) creatinine clearances, respectively; and 90 mg/d of protein for proteinuria (n = 556). The prevalence of mild renal dysfunction (creatinine clearance </= 60 mL/min/1.73 m(2)) was nearly 11%. In single-gene analyses with adjustment for significant covariables, the risk for mild renal dysfunction was positively associated with the ACE D allele. However, multiple-gene analyses showed that these associations were restricted to carriers of the mutated alpha-adducin Trp allele (40.1% of all subjects). Findings remained similar after hypertensive patients and women on hormonal therapy were excluded. In this phenotypically more homogeneous subgroup, serum creatinine level was 3.6 micromol/L (P = 0.02) and relative risks for mild renal dysfunction and proteinuria were 1.7-fold (P < 0.001) and 26% (P = 0.02) greater in ACE D subjects than ACE II homozygotes, respectively. The aldosterone synthase T allele did not strengthen genetic associations with the ACE D allele considered alone or in combination with the alpha-adducin Trp allele. Thus, in the present cross-sectional analysis, renal function was slightly but consistently impaired when both the ACE D and alpha-adducin Trp alleles were present. These findings, together with experimental studies and our previous reports on femoral intima media thickness and the incidence of hypertension, constitute a growing body of evidence delineating a clinical entity genetically determined by the risk-carrying ACE D and alpha-adducin Trp alleles.
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PMID:Renal function in relation to three candidate genes. 1172 46

An interaction effect between the angiotensin-converting enzyme insertion/deletion (ACE I/D) and alpha-adducin (ADD1) Gly460Trp polymorphisms (G460W) on blood pressure regulation has recently been suggested, although its significance in the prognosis of renal function in IgA nephropathy (IgAN) has not been fully investigated. Therefore, we evaluated the clinical manifestations and renal prognosis in 276 Japanese patients with histologically proven IgAN with respect to their ACE I/D and ADD1 G460W polymorphisms. The prognosis of renal function was analyzed by Kaplan-Meier survival curves and multivariate Cox proportional-hazards regression models. Baseline data, including blood pressures, proteinuria, renal function, and incidence of hypertension, were similar for the different genotypes of ACE and ADD1. The individual genotypes taken alone were not associated with the progression of renal dysfunction. However, renal survival of patients with the 460WW polymorphism of ADD1 was significantly worse within the group with the II genotype of ACE (Kaplan-Meier, log rank test; chi2=6.062, P=0.0138) but not for those with other ACE genotypes. In the Cox proportional-hazards regression model with adjustment for clinical risk factors, including hypertension, proteinuria, and no administration of an angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers, the 460WW variant of ADD1 was a highly significant and independent risk factor only for patients with the ACE II genotype, with a hazard ratio of 3.65 (P=0.0016), but not for those with other ACE genotypes (hazard ratio=0.65, P=0.2902). These findings suggest an interaction between ACE and ADD1 polymorphisms not only on blood pressure regulation but also on the progression of renal dysfunction in patients with IgAN.
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PMID:Interaction between ACE and ADD1 gene polymorphisms in the progression of IgA nephropathy in Japanese patients. 1288 93

Until recently elevated blood pressure was considered as a hemodynamic entity representing an increase in workload for the heart and the arterial tree. Control of hypertension meant hemodynamic unloading, through inhibition of vasoconstrictor pathways, principally renin-angiotensin system and sympathetic system. In recent years however a new pharmacological approach has evolved as a result of (i) the dissociation of endothelial dysfunction and vascular pathology from increased blood pressure; (ii) the recognition that endothelial dysfunction regards not only the vascular reactivity, but also promotes atherosclerosis and thrombosis; and (iii) an improved understanding of the complexity of local-tissue renin angiotensin system and of the vasodilatory and cytoprotective role of natriuretic peptides. This has led to a reconsideration of existing medicines in terms of specification on endothelial function, more rationalized application of drugs and search for new compounds targeting both vasodilatory and anti-proliferative pathways. Examples include beta1-adrenergic antagonists, such as Nebivolol and Carvedilol, and vasopeptidase inhibitors, such as Omapatrilat, that inhibit simultaneously the angiotensin converting enzyme and neutral endopeptidase. Furthermore the identification of genetic polymorphisms in the effectors involved in the pathophysiology of hypertension or in the response to anti-hypertensive drugs, such as the p22phox subunit of NADPH oxidase, alpha-adducin or adrenergic receptors, has promoted the prospective of both better understanding of hypertension and individualized strategies for its treatment.
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PMID:The shift in the "paradigm" of the pharmacology of hypertension. 1496 15

The blood pressure (BP) response to any single antihypertensive drug is characterized by marked interindividual variation, and the known predictors of response are of limited value in identifying the optimum drug for an individual patient. Analysis of genetic variation has the potential to improve our understanding of determinants of antihypertensive drug response in order to individualize drug selection. Genetic variation can influence both pharmacokinetic and pharmacodynamic mechanisms underlying variation in drug response. Classic pharmacogenetic investigations have identified variations in single genes that have a large effect on antihypertensive drug metabolism and are inherited in a Mendelian fashion. These include a polymorphism in the CYP2D6 gene, encoding a cytochrome p450 family member involved in phase I drug metabolism, and polymorphisms in genes encoding enzymes involved in phase II drug metabolism, including N-acetyltransferase (NAT2), catechol-O-methyltransferase (COMT), and phenol sulfotransferase (P-PST, SULT1A1). Although these polymorphisms have major effects on the pharmacokinetic profiles of both commonly used antihypertensive drugs such as metoprolol (CYP2D6), and lesser used drugs such as hydralazine (NAT2), methyldopa (COMT), and minoxidil (SULT1A1), they have not been shown to influence variation in the antihypertensive effect of these drugs at conventional doses. Interest is now focused on identifying genetic polymorphisms that influence the pharmacodynamic determinants of antihypertensive response. Using a candidate gene approach, such polymorphisms have been identified in genes encoding alpha-adducin (ADD1), subunits of G-proteins (GNB3 and GNAS1), the beta(1)-adrenergic receptor (ADRB1), endothelial nitric oxide synthase (NOS3), and components of the renin-angiotensin-aldosterone system (angiotensinogen [AGT], angiotensin converting enzyme [ACE], the angiotensin type I receptor [AGTR1], and aldosterone synthase [CYP11B2]). These polymorphisms have been shown to influence the BP response to diuretics (ADD1, GNB3, NOS3, and ACE), beta-blockers (GNAS1 and ADRB1), ACE inhibitors (AGT, ACE, and AGTR1), angiotensin receptor blockers (ACE and CYP11B2), and clonidine (GNB3).An emerging consensus from these studies is that single gene effects on antihypertensive drug responses are small, and even the combined effects of all presently known polymorphisms do not account for enough variation in response to be clinically useful. New genome-wide scanning techniques may lead to the identification of genes previously unsuspected of influencing drug response. Additional requirements for pharmacogenetic approaches to become clinically useful are the characterization of the effects of haplotypes and multi-locus genotypes on drug response, and consideration of gene-by-environment interactions. Such studies will require huge sample sizes and novel statistical methods, but the theoretical and technical framework is in place to make this possible.
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PMID:Pharmacogenetics of antihypertensive drug responses. 1517 96

Genetic factors may influence the response to antihypertensive medication. A number of studies have investigated genetic polymorphisms as determinants of cardiovascular response to antihypertensive drug therapy. In most candidate gene studies, no such drug-gene interactions were found. However, there is observational evidence that hypertensive patients with the 460 W allele of the alpha-adducin gene have a lower risk of myocardial infarction and stroke when treated with diuretics compared with other antihypertensive therapies. With regard to blood pressure response, interactions were found between genetic polymorphisms for endothelial nitric oxide synthase and diuretics, the alpha-adducin gene and diuretics, the alpha-subunit of G protein and beta-adrenoceptor antagonists, and the ACE gene and angiotensin II type 1 (AT(1)) receptor antagonists. Other studies found an interaction between ACE inhibitors and the ACE insertion/deletion (I/D) polymorphism, which resulted in differences in AT(1) receptor mRNA expression, left ventricular hypertrophy and arterial stiffness between different genetic variants. Also, drug-gene interactions between calcium channel antagonists and ACE I/D polymorphism regarding arterial stiffness have been reported. Unfortunately, the quality of these studies is quite variable. Given the methodological problems, the results from the candidate gene studies are still inconclusive and further research is necessary.
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PMID:Drug-gene interactions between genetic polymorphisms and antihypertensive therapy. 1530 63


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