Jens Ringel

Genetic variants of the renin-angiotensin system, diabetic nephropathy and hypertension

Summary Recent studies have suggested an association between a deletion (D) variant of the angiotensin-converting-enzyme (ACE) gene and diabetic nephropathy. However, this finding has not been confirmed by all investigators. Furthermore, an M235T variant of the angiotensinogen (AGT) gene has been associated with hypertension, an important risk factor for the development and progression of diabetic nephropathy. The objective of our study was therefore to examine the relationship between these genetic variants of the renin-angiotensin system and diabetic nephropathy and hypertension, respectively, in a large (n = 661) group of Caucasian patients with insulin-dependent (n = 360) or non-insulin-dependent (n = 301) diabetes mellitus. The study had a power of 0.8 to detect a doubling of risk of nephropathy or hypertension in patients with the ACE-DD or AGT-235TT genotype, respectively. Allelic frequencies of the ACE-D and AGT-235T alleles were similar between patients with and without nephropathy in either type of diabetes, and accordingly, there was no significant association between diabetic nephropathy and the ACE or AGT genotype. Likewise, there was no significant association between the ACE or AGT genotype and hypertension. Thus, our data, in this large and ethnically homogeneous group of patients, do not support the hypothesis that these genetic variants of the renin-angiotensin system are strongly associated with either nephropathy or hypertension in patients with insulin-dependent or non-insulin-dependent diabetes mellitus. These genetic markers are therefore unlikely to serve as clinically useful predictors of either nephropathy or hypertension in Caucasian patients with diabetes. [Diabetologia (1997) 40: 193–199]

The Trp64Arg polymorphism of the β3-adrenergic receptor gene is associated with hypertension in men with type 2 diabetes mellitus

Abstract A missense mutation of the β3-adrenergic receptor gene (ADRB3) resulting in a tryptophan/arginine exchange at position 64 (Trp64Arg polymorphism) has recently been associated with greater capacity to gain weight, a low resting metabolic rate, higher blood pressure, and an early onset of type 2 diabetes. These findings prompted us to examine the relationship between this mutation, blood pressure, and vascular complications in German patients with type 2 diabetes. White patients with type 2 diabetes mellitus (n = 417) were enrolled in the study. The Trp64Arg polymorphism of the ADRB3 gene was detected by polymerase chain amplification and subsequent restriction digest with BstN I. Stepwise logistic regression analysis of the entire study population revealed a significant interaction between gender and genotype (P = .019). We therefore performed separate analyses for men and women. There was a significant relationship between hypertension and the ADRB3 Trp64Arg variant in men (P = .015), but not in women. Furthermore, blood pressure levels in male patients with the minor allele had higher blood pressure levels (P In conclusion, our data are compatible with a contribution of this genetic variant of ADRB3 to hypertension in male patients with type 2 diabetes. Further studies will be needed to determine the role of this polymorphism as a predictor of hypertension or vascular complications in patients with type 2 diabetes.

Hpa II polymorphism of the atrial natriuretic peptide gene and the blood pressure response to salt intake in normotensive men.

Objective To test the hypothesis that the Hpa II variant of the atrial natriuretic peptide gene (ANP), which has been reported to be more common among black hypertensives than it is among normotensive controls, is related to the response of blood pressure to salt intake in normotensive Caucasians. Methods One hundred and three young (aged 19–35 years) male volunteers were fed a low-salt diet (20 mmol NaCl/day) for 2 weeks and a supplement of either 200 mmol NaCl/day (slow sodium) or placebo for 1 week each in a randomized double-blind cross-over order. Salt sensitivity was defined as a significant (P < 0.05) decrease in resting mean arterial blood pressure by > 3 mmHg under the low-salt diet. The genotype was determined by amplification of genomic DNA extracted from peripheral leukocytes and subsequent digestion of the amplicon with Hpa II restriction enzyme. Results According to the above definition, 27 subjects were salt sensitive. There were no significant differences in age, body-mass index and waist: hip ratio between the salt-sensitive and salt-resistant groups. Only salt-sensitive subjects displayed a significantly higher blood pressure under the high-salt diet (increase in mean arterial pressure 5.6 ± 2.4 mmHg, P < 0.001). The prevalence of the ANP-Hpa II wild-type (w) allele did not differ between the salt-sensitive (qw = 1.0, qm = 0) and the salt-resistant group (qw = 0.96, qm = 0.04). Furthermore, the salt-induced response of blood pressure did not differ between homozygotes (ww) and heterozygotes (wm). Conclusions Our findings do not support the hypothesis that the ANP-Hpa II polymorphism is a marker for salt sensitivity in young Caucasian normotensives.

Genetic variants of the renin-angiotensin system and ambulatory blood pressure in essential hypertension.

Objective To examine whether the angiotensinogen M235T and angiotensin converting enzyme insertion/deletion (I/D) variants are related to the severity of hypertension in patients with established essential hypertension. Design A cross-sectional study. Setting The hypertension clinic of the Benjamin Franklin University Hospital, Free University of Berlin. Participants Three hundred and forty-three consecutive Caucasian patients who presented with treated or untreated (n = 115) hypertension were enrolled into the study. Twenty-two patients were excluded from analysis because they had secondary hypertension. Main outcome measures Angiotensinogen M235T and angiotensin-converting enzyme I/D genotypes, 24 h ambulatory blood pressure values, the number of antihypertensive medications administered and left ventricular dimensions assessed by two-dimensional echocardiography. Results Neither the angiotensinogen nor the angiotensin converting enzyme genotype was related significantly to the average ambulatory blood pressure and left ventricular dimensions in hypertensives. Furthermore, neither the number of antihypertensive medications administered to treated patients nor blood pressure levels in untreated patients (n = 115) differed significantly between the genotypic groups. Conclusions These results do not support the hypothesis that the studied molecular variants of the renin–angiotensin system may represent clinically useful markers of the severity of hypertension in Caucasians with established essential hypertension.

Die Rolle des Angiotensinogengens für die essentielle Hypertonie

ZusammenfassungDie essentielle Hypertonie wird als komplexes heterogenes Krankheitsbild sowohl von Umweltfaktoren als auch von genetischen Determinanten geprägt. Der Einfluß des Renin-Angiotensin-Systems auf die Blutdruckregulation ist bekannt.Angiotensinogen spielt als Vorläufer des biologisch aktiven Angiotensin II eine entscheidende Rolle. Initiale Untersuchungen an hypertonen Geschwisterpaaren und Fallkontrollstudien zeigten eine besondere Bedeutung des Angiotensinogengens für die Prädisposition zur essentiellen Hypertonie, Präeklampsie und adipositasassoziierten Hypertonie. Neben der bisherigen Identifizierung zahlreicher Polymorphismen und deren Untersuchung in Fallkontrollstudien ist das Ziel aktueller Studien die Analyse möglicher funktioneller Angiotensionogengenvarianten (C-532T, G-6A), welche für die Regulation der Genexpression und damit Angiotensinogengenerierung verantwortlich sein können. Das A-6-Allel steht in komplettem Kopplungsungleichgewicht mit dem T235-Allel und ist mit einer erhöhten Angiotensinogengenexpression in vitro assoziiert. Segregations-Kopplungs-Analysen zeigen, daß der C-532T-Polymorphismus die Plasmaangiotensinogenvariabilität mit noch stärkerer Signifikanz als G-6A beeinflußt. Wegen der Lokalisation des C-532T-Polymorphismus in einem AP-2-Konsensuselement sind nachfolgende Promotorfunktionsanalysen von besonderem Interesse.Das Verständnis der molekulargenetischen Basis des Renin-Angiotensin-Systems für die essentielle Hypertonie könnte zur Entwicklung neuer pharmakologischer Ansätze und möglicherweise zu einer individuelleren antihypertensiven Therapie beitragen.AbstractEssential hypertension is a complex disease influenced by different genetic and environmental factors. The renin-angiotensin system (RAS) is implicated in blood pressure regulation.Angiotensinogen (AGT) is the precursor of the biologically active angiotensin II (Ang II). Initial studies on hypertensive siblings and case-control studies indicated the important role of the angiotensinogen gene (AGT) for the predisposition to essential hypertension, preeclampsia and obesity-related hypertension. Recently, differentAGT polymorphisms had been identified and analyzed in case-control studies. The aim of present studies is the analysis of potentially functionalAGT variants (C-532T, G-6A), which might be responsible for the regulation of gene expression and therefore AGT generation. The A-6 allele is in complete linkage disequilibrium with the T235 allele and is associated with higher AGT expression in vitro. Segregation linkage analysis demonstrated that the C-532T polymorphism influences plasma AGT variability more significantly than the G-6A variant. Since the C-532T polymorphism is located within a AP-2 consensus element, functional promoter analyses are required.The understanding of the molecular basis of RAS in essential hypertension may provide us with new and more specific pharmacological agents and perhaps the ability to individualize antihypertensive treatment.Essential hypertension is a complex disease influenced by different genetic and environmental factors. The renin-angiotensin system (RAS) is implicated in blood pressure regulation. Angiotensinogen (AGT) is the precursor of the biologically active angiotensin II (Ang II). Initial studies on hypertensive siblings and case-control studies indicated the important role of the angiotensinogen gene (AGT) for the predisposition to essential hypertension, preeclampsia and obesity-related hypertension. Recently, different AGT polymorphisms had been identified and analyzed in case-control studies. The aim of present studies is the analysis of potentially functional AGT variants (C-532T, G-6A), which might be responsible for the regulation of gene expression and therefore AGT generation. The A-6 allele is in complete linkage disequilibrium with the T235 allele and is associated with higher AGT expression in vitro. Segregation linkage analysis demonstrated that the C-532T polymorphism influences plasma AGT variability more significantly than the G-6A variant. Since the C-532T polymorphism is located within a AP-2 consensus element, functional promoter analyses are required. The understanding of the molecular basis of RAS in essential hypertension may provide us with new and more specific pharmacological agents and perhaps the ability to individualize antihypertensive treatment.

Non-pharmacological treatment of hypertension: a survey of 2150 general practitioners and internists.

Non-pharmacological treatment is widely recommended both as the initial approach for the management of mild hypertension and as an adjunct to all forms of drug therapy. There is, however, little information about the attitude and approach of physicians in private practices to non-pharmacological measures for the treatment of hypertension. We therefore examined the attitude and approach of German general practitioners and internists to non-pharmacological treatment of hypertension in a random sample of 2150 physicians in private practices, selected from the physicians’ registry of Berlin (n = 2100) and Bonn (n = 50). All participants were requested to complete a questionnaire concerning non-pharmacological treatment of hypertension. Data were analysed by descriptive statistics, and responses were compared between general practitioners and internists by xanalysis. Two-hundred and seventy-four general practitioners (21.4%) and 188 internists (21.5%) responded