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)

A molecular variant of the angiotensinogen gene with threonine instead of methionine at position 235 (ie, with M235T polymorphism) has been shown to be associated with essential hypertension in Caucasian populations. The purpose of the present study was to assess whether the M235T polymorphism was associated with essential hypertension in the Japanese population. The study population consisted of 347 subjects selected in our outpatient clinic. The clinical data included in the analyses were sex, age, body mass index, cholesterol level, genotype of the angiotensinogen gene, genotype of the angiotensin-converting enzyme gene, and systolic and diastolic blood pressure. Multiple regression analysis revealed that only body mass index was a predictor of both diastolic and systolic blood pressure in these 347 subjects, but the genotype of the angiotensinogen gene was identified as a predictor of both diastolic and systolic blood pressure in a subpopulation less than 50 years of age. However, in a subpopulation more than 50 years of age, body mass index was the only predictor of both systolic and diastolic blood pressure. Of the 347 subjects, 189 had a technically excellent echocardiogram at the initial observation period. Multiple regression analysis revealed that sex, body mass index, diastolic blood pressure, and genotype of the angiotensin-converting enzyme gene were predictors of left ventricular mass. Although subjects with the TT angiotensinogen genotype had significantly greater left ventricular mass than those with either the TM or the MM genotype, the effects of the genotype of the angiotensinogen gene on left ventricular mass were mainly due to effects on blood pressure.
Hypertension 1995 Apr
PMID:Angiotensinogen gene and blood pressure in the Japanese population. 772 17

To explore the genes responsible for myocardial infarction and restenosis after percutaneous transluminal coronary angioplasty, we performed association studies of the polymorphisms of the angiotensinogen and angiotensin-converting enzyme (ACE) genes. In the first study, normotensive myocardial infarction patients (n = 103) and control subjects (n = 103), who were matched for established risk factors with the myocardial infarction patients, were randomly selected. The angiotensinogen-TT genotype (T indicates threonine instead of methionine at position 235) was more frequent in the myocardial infarction group than in the control group (P < .05). The ACE-DD genotype (D indicates a deletion polymorphism in intron 16) was also more frequent in the myocardial infarction group (P < .0001). The odds ratio estimated by the combined analysis of the angiotensinogen-TT and ACE-DD genotypes (11.2) was markedly increased compared with that estimated separately from the angiotensinogen-TT (1.75) or ACE-DD (4.43) genotype. In the second study, we investigated 91 consecutive patients with acute myocardial infarction who underwent successful direct angioplasty. Combined analysis showed that the angiotensinogen-TT genotype did not enhance the predictability of myocardial infarction from the ACE-DD genotype. In conclusion, the angiotensinogen-TT genotype is a predictor for myocardial infarction, as well as the ACE-DD genotype, and the combined analysis of the angiotensinogen-TT and ACE-DD genotypes further enhanced the predictability of myocardial infarction in Japanese, suggesting its future clinical usefulness.
Hypertension 1995 May
PMID:Enhanced predictability of myocardial infarction in Japanese by combined genotype analysis. 773 32

Several genes, including some encoding components of the renin angiotensin system, are associated with the risk of cardiovascular diseases. There have been reports linking a homozygous deletion allele of the angiotensin converting enzyme (ACE) gene (DD) with an increased risk of myocardial infarction, and some variants of the angiotensinogen gene with an increased risk of hypertension. In a case-control study of a caucasian population from New Zealand, we examined the associations with coronary heart disease (CHD) of ACE DD and of a mis-sense mutation with methionine to threonine aminoacid substitution at codon 235 in the angiotensinogen gene (T235). We studied 422 patients (mean age 62 years, 81% male) with documented CHD (50% with myocardial infarction) and 406 controls without known CHD (frequency-matched to cases by age and sex). Risk factors for CHD were assessed by standard questionnaire, physical examination, and blood tests. Genomic DNA from leucocytes was analysed for various ACE and angiotensinogen alleles. Angiotensinogen T235 homozygotes were at significantly increased risk of CHD generally (odds ratio 1.7, 2 p = 0.008) and of myocardial infarction specifically (1.8, 2 p = 0.009). Adjustment for several risk factors increased the estimate of CHD risk associated with this allele to 2.6 (2 p < 0.001) and the estimate for myocardial infarction risk to 3.4 (2 p < 0.001). By contrast, there was no evidence of a significant increase in the risk of CHD or myocardial infarction among individuals with ACE DD. We conclude that the T235 polymorphism of the angiotensinogen gene is an independent risk factor, which carries an approximately two-fold increased risk of CHD. In this study, however, ACE DD was not associated with any detectable increase in CHD risk.
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PMID:Association of angiotensinogen gene T235 variant with increased risk of coronary heart disease. 763 19

We have previously reported increased activity of Na+/H+ and Na+/Li+ exchanges in red blood cells (RBC) of patients with hypertension and diabetic nephropathy. The presence in human red blood cells (RBC) of insulin receptors has led us to examine the effects of this hormone on the kinetic parameters of Na+/H+ exchange as a first approach to define its mechanism of action. The antiporter activity was measured as net Na+ influx driven by an outward H+ gradient in acid-loaded, Na-depleted RBCs preincubated with or without (w/wo) insulin (0 to 100 microU/ml) for different time periods. The effects of insulin on the H+ and Na+ activation kinetics of Na+/H+ exchange were examined in RBCs of normal subjects fasted for 12 hours. Insulin (50 microU/ml for 1 hr) increased the Vmax from 28 +/- 6 to 49 +/- 8 mmol/liter cell x hr (N = 10, P < 0.0005) and the Km for Na+ from 72 +/- 10 to 142 +/- 19 mM (N = 4, P < 0.05) but did not change the Km for intracellular H+. Insulin also increased the Vmax of Na+/Li+ exchange at pHi 7.4 (0.34 +/- 0.03 to 0.45 +/- 0.04 mmol/liter cell x hr, N = 9, P < 0.005) as well as the Km for Na+ (31 +/- 3 to 6 +/- 10 mM, P < 0.0003). Therefore, insulin can modulate Na+ sites of Na+/Li+ or Na+/H+ exchanges independent of the occupancy of H+ sites to favor the release of bound Na+ into the cytoplasm. Insulin stimulation of Na+/H+ exchange required endogenous cytosolic Ca2+ levels. The kinetic effects of insulin on Na+/H+ and Na+/Li+ exchanges were imitated by okadaic acid (300 microM), an inhibitor of protein phosphatases which dephosphorylate serine-threonine residues. Okadaic acid increased the Vmax of Na+/H+ and Na+/Li+ exchanges and the Km for Na+ as insulin did. In conclusion, insulin stimulation of the Na+/H+ antiporter occurs by a novel kinetic mechanism leading to a decreased affinity for external Na+ without changes in the affinity for Hi. On the basis that insulin effects were imitated by okadaic acid, we hypothesize that this hormone may increase the phosphorylated state of serine-threonine residues of this antiporter protein.
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PMID:Insulin activation of red blood cell Na+/H+ exchange decreases the affinity of sodium sites. 796 48

Agonist-induced receptor phosphorylation plays a role in transmembrane signal transduction systems. Although the cDNA for the rat vascular type 1 angiotensin II receptor (AT1AR) encodes a G protein-coupled receptor with several potential phosphorylation sites for serine/threonine and tyrosine kinases, little is known about the phosphorylation of this receptor. The aim of this study was to determine the effects of angiotensin II (Ang II) on phosphorylation of the AT1AR in rat aortic vascular smooth muscle cells. Using [32P]orthophosphate-labeled cells, immunoprecipitates with anti-AT1AR antibody revealed a labeled band of molecular weight 52 kD, corresponding to the Ang II receptor. Ang II induced a rapid and significant increase in phosphorylation of the Ang II receptor, with a peak at 20 minutes. Phosphoamino acid analysis showed that the major phosphoamino acid is serine, in both the basal and Ang II-stimulated states. Constitutive and agonist-stimulated tyrosine phosphorylation is also observed to a lesser extent. Immunoblotting of anti-phosphotyrosine immunoprecipitates with anti-AT1AR antibody showed that Ang II caused a delayed tyrosine phosphorylation of the receptor with a peak at 20 minutes in a dose-dependent manner. Forskolin increased total phosphorylation of AT1AR but had no effect on tyrosine phosphorylation. Neither phorbol 12-myristate-13-acetate nor ionomycin altered receptor phosphorylation. These findings suggest that Ang II induces the phosphorylation of its own G protein-coupled receptor through both serine and tyrosine kinases and raise the possibility that phosphorylation of the AT1AR is an important regulator of receptor function.
Hypertension 1994 Oct
PMID:Agonist-induced phosphorylation of the vascular type 1 angiotensin II receptor. 808 22

Genetic influences in cerebrovascular disease (CVD) may act either independently or by predisposing to, or modulating, the effect of risk factors such as hypertension. Factors involved in the pathogenesis of atherosclerosis, thrombosis and vasoconstriction are important in CVD. The angiotensinogen gene has recently been linked with essential hypertension in affected sibships and a particular polymorphism in exon 2 of the angiotensinogen gene, a threonine to methionine substitution at position 235 (M235T), has been associated with pre-eclampsia and hypertension. In this study we examined the relation of M235T polymorphism to cerebrovascular disease and carotid atheroma in 100 consecutive Caucasian patients with internal carotid artery territory ischaemia (TIA or stroke), presenting to a carotid ultrasound service. Forty five age-matched controls (mostly patients' spouses) were also studied. Hypertension was defined as current treatment with anti-hypertensive agents, or SBP > 160 mm Hg or DBP > 95 mm Hg. Twelve of 100 cases (12%) and eight of 45 controls (12%) were homozygous for the T235 allele. T:M allele ratios were 0.34:0.66 in cases and 0.34:0.66 in controls. There was no relation between the polymorphism and either internal carotid stenosis or common carotid artery intima-media thickness. In the cases, mean percentage internal carotid artery stenosis was TT 18.3 (SD 18.7)%, MT 38.0 (27.1)% and MM 36.8 (30.2)%. Mean intima-media thickness was TT 0.87 (0.18) mm, MT 0.95 (0.34) mm and MM 0.88 (0.23) mm. There was no relation between the polymorphism and hypertension (TT 11 of 100 cases, six of 45 controls).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lack of association between angiotensinogen polymorphism (M235T) and cerebrovascular disease and carotid atheroma. 852 90

Genotypic abnormalities of the renin-ANG system have been suggested as a risk factor for the development of diabetic nephropathy. Cleavage of angiotensinogen is the rate-limiting step in the activation of the renin-ANG system. The TT genotype of a polymorphism encoding threonine instead of methionine (M235T) has been associated not only with increased plasma angiotensinogen concentration but also with essential hypertension. In addition, a polymorphism in the angiotensinogen gene substituting methionine for threonine (T174M) has been associated with hypertension in nondiabetic populations. We studied the relationship between these polymorphisms in the angiotensinogen gene in IDDM patients with diabetic nephropathy (121 men, 74 women, age 40.9 +/- 10 years, diabetes duration 27 +/- 8 years). There was no difference in M235T genotype distribution between IDDM patients with diabetic nephropathy and those with normoalbuminuria: 73/97/25 (37/50/13%) vs. 67/95/23 (36/52/12%) had MM/MT/TT genotypes, respectively. No difference in distribution of T174M genotypes between nephropathic and normoalbuminuric IDDM patients was observed either: 148/44/1 (77/23/0.5%) vs. 141/42/2 (76/23/1%) had TT/TM/MM genotypes, respectively. In patients with nephropathy, systolic blood pressure was higher (161 +/- 22 mmHg [mean +/- SD]) in patients carrying TT genotype of the M235T angiotensinogen polymorphism as compared with patients with MM or MT genotypes (150 +/- 23 mmHg; P = 0.03). We conclude that neither the M235T nor the T174M polymorphism in the angiotensinogen gene contributes to genetic susceptibility to diabetic nephropathy in white IDDM patients, whereas the TT genotype of the M235T is associated with elevated blood pressure in patients with diabetic nephropathy.
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PMID:Angiotensinogen gene polymorphisms in IDDM patients with diabetic nephropathy. 859 44

The allele 235T (a threonine in place of a methionine at position 235) of angiotensinogen has been found to be associated with a predisposition to essential hypertension. We investigated whether this allele also confers increased susceptibility to nephropathy in patients with insulin-dependent diabetes mellitus (IDDM). A group of 380 patients who had had IDDM for 15 to 20 years were genotyped at the angiotensinogen 235 locus. Included were 75 patients with normoalbuminuria (albumin excretion rate < 30 micrograms/min), two series of patients with microalbuminuria (n = 30 and n = 136), and two series with overt proteinuria (n = 41 and n = 98). Allele 235T frequency was higher among cases with microalbuminuria (0.41 in the two series combined) or overt proteinuria (0.40) than in the normoalbuminuria group (0.36). However, this difference was not statistically significant with this sample size (chi 2 = 1.2, P = NS with 2 df). Under a recessive model, allele 235T homozygotes had a 1.6-fold risk of developing nephropathy relative to carriers of other genotypes, but this value was not significantly different from 1(95% CI = 0.8 to 3.5). The strength of the association did not improve after stratification by degree of glycemic control. With respect to the hypertension in these IDDM patients, no association with allele 235T was found. Allele 235T frequencies in normotensive and hypertensive individuals were 0.363 and 0.353, respectively, among normoalbuminuric IDDM individuals (chi 2 = 0.01, P = NS) and 0.411 and 0.414 among microalbuminuric IDDM subjects (chi 2 = 0.0, P = NS). We conclude that the angiotensinogen polymorphism M235T might influence susceptibility to nephropathy in insulin-dependent diabetes, but its effect, if any, is rather small and independent of hypertension.
Hypertension 1996 May
PMID:Angiotensinogen polymorphism M235T, hypertension, and nephropathy in insulin-dependent diabetes. 862 Dec 7

Since the renin angiotensin system (RAS) is established as an important factor in renal disease progression, we determined whether RAS alleles that have been linked to variability in outcome in several cardiovascular diseases also affect progression of IgA nephropathy. These genetic variants include: (1) angiotensin I converting enzyme deletion polymorphism in intron 16 (ACE I/D), reported to be associated with increased risk of myocardial infarction as well as left ventricular hypertrophy; (2) a point mutation in the angiotensinogen (Agt) gene resulting in a methionine to threonine substitution at residue 235 (M235T), reported to be associated with hypertension in Caucasians; and (3) an angiotensin receptor type I (ATR) A to C transition at bp 1166 (A1166C) which shows synergy with the deleterious effects of the ACE DD genotype in myocardial infarction. We examined these polymorphisms by PCR amplification of genomic DNA samples from 64 Caucasian patients in the USA (age 6 to 83 years) with biopsy-proven IgA nephropathy whose renal status was followed for an average of almost seven years. Patients who presented with and maintained normal serum creatinine (Cr, < 1.5 mg/dl), had ACE genotype frequencies of II:35%, ID:61%, DD:4%. By contrast, in patients with progression (initially normal Cr increased to a mean of 4.5 +/- 0.86 mg/dl), ACE genotype frequencies were II:22%, ID:44%, DD:33% (P = 0.057 by Fishers's exact test, vs. non-progressors). The association of the DD genotype with progression was even more striking when patients with other risk factors (hypertension and/or heavy proteinuria) were excluded. In this subgroup, the genotype frequencies in patients with stable creatinine versus those with deterioration in renal function was 53%, 47%, and 0% versus 0%, 40%, and 60%, respectively, for II, ID, and DD genotypes (P = 0.009 by Fisher's exact test, progressors vs. non-progressors). Further, sequence analysis of the I gene polymorphism revealed a potential 13 bp silence motif. Neither the Agt 235T nor the ATR A 1166C gene variants, however, was associated with deterioration of renal function. Taken together, these results indicate that, although polymorphism in each of the three genes in the RAS system has been linked to cardiovascular diseases, only the ACE I/D polymorphism is associated with progressive deterioration in renal function in IgA nephropathy. Since previous observations link ACE polymorphism with ACE activity, these findings imply a widespread importance of ACE in modulating destructive processes in different organs.
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PMID:Angiotensin converting enzyme gene polymorphism: potential silencer motif and impact on progression in IgA nephropathy. 882 46

Premature cardiovascular disease is common in insulin-dependent diabetic (IDDM) patients who develop diabetic nephropathy. Genetic polymorphism within the renin-angiotensin system has been implicated in the aetiology of a number of cardiovascular disorders; these loci are therefore candidate genes for susceptibility to diabetic renal disease. We have examined the angiotensin converting enzyme insertion/deletion polymorphism and angiotensinogen methionine 235 threonine polymorphism in a large cohort of Caucasian patients with IDDM and diabetic nephropathy. Patients were classified as having nephropathy by the presence of persistent dipstick positive proteinuria (in the absence of other causes), retinopathy and hypertension (n = 242). Three groups were examined for comparison: ethnically matched non-diabetic subjects (n = 187); a geographically defined cohort of newly diagnosed diabetic patients (n = 341); and IDDM patients with long duration of disease (> 15 years) and no evidence of overt nephropathy (n = 166). No significant difference was seen in distribution of angiotensin converting enzyme or angiotensinogen genotypes between IDDM patients with nephropathy and recently diagnosed diabetic subjects (p = 0.282 and 0.584, respectively), nor the long-duration non-nephropathy diabetic subjects (p = 0.701 and 0.190, respectively). We conclude that these genetic loci are unlikely to influence susceptibility to diabetic nephropathy in IDDM in the United Kingdom.
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PMID:Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM. 887 96


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