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OBJECTIVE--Genetic and environmental factors modulate the susceptibility to diabetic nephropathy, as initiating and/or progression factors. The objective of the European Rational Approach for the Genetics of Diabetic Complications (EURAGEDIC) study [...]

The Pro12Ala polymorphism of the gene encoding the peroxisome proliferator-activated receptor (PPAR)-γ2 has recently been shown to be associated with type 2 diabetes. In the present analysis, we investigated whether PPAR-γ2 Pro12Ala was associated with microvascular complications of type 2 diabetes, such as albuminuria, end-stage renal failure (ESRF), or retinopathy. A total of 445 patients with type 2 diabetes who were enrolled in the Berlin Diabetes Mellitus Study and in whom we determined albuminuria and the presence of ESRF and retinopathy were genotyped for the PPAR-γ2 Pro12Ala polymorphism. We also measured potentially important covariables, such as blood pressure, BMI, duration of diabetes, glycosylated hemoglobin, serum creatinine, and serum lipids. Among 445 patients with type 2 diabetes (mean age 59.3 years), the Pro12Ala genotype distribution was in Hardy-Weinberg equilibrium (P = 0.42). The Ala12 allele frequency was 0.14. With adjustment for covariables, the 118 Ala12 allele carriers had significantly lower urinary albumin excretion (UAE) than the 327 noncarriers (17.1 vs. 25.8 mg/d; P = 0.01). The percentage decrease in UAE observed in PPAR-γ Ala12 allele carriers relative to noncarriers (P = 0.003) rose from 0.2% (P = 0.99) to 54% (P = 0.008) and to 70% (P = 0.01) when the duration of diabetes increased from, Type2 diabetes constitutes a major health problem and in most populations substantially contributes to morbidity and mortality (1). Its complications include macrovascular disorders such as coronary artery disease (CAD) and [...]

BackgroundPatients with Fabry disease (FD) on reduced dose of agalsidase-beta or after switch to agalsidase-alfa show a decline in chronic kidney disease epidemiology collaboration-based estimated glomerular filtration rate (eGFR) and a worsened plasma lyso-Gb3 decrease. Hence, the most effective dose is still a matter of debate.MethodsIn this prospective observational study, we assessed end-organ damage and clinical symptoms in 78 patients who had received agalsidase-beta (1.0 mg/kg) for >1 year, which were assigned to continue this treatment (agalsidase-beta, regular-dose group, n=17); received a reduced dose of agalsidase-beta and subsequent switch to agalsidase-alfa (0.2 mg/kg) or a direct switch to 0.2 mg/kg agalsidase-alfa (switch group, n=22); or were re-switched to agalsidase-beta after receiving agalsidase-alfa for 12 months (re-switch group, n=39) with a follow-up of 88±25 months.ResultsNo differences for clinical events were observed for all groups. Patients within the re-switch group started with the worst eGFR values at baseline (p=0.0217). Overall, eGFR values remained stable in the regular-dose group (p=0.1052) and decreased significantly in the re-switch and switch groups (p<0.0001 and p=0.0052, respectively). However, in all groups males presented with an annual loss of eGFR by –2.9, –2.5 and −3.9 mL/min/1.73 m² (regular-dose, re-switch, switch groups, all p<0.05). In females, eGFR decreased significantly only in the re-switch group by −2.9 mL/min/1.73 m² per year (p<0.01). Lyso-Gb3 decreased in the re-switch group after a change back to agalsidase-beta (p<0.05).ConclusionsOur data suggest that a re-switch to high dosage of agalsidase results in a better biochemical response, but not in a significant renal amelioration especially in classical males.

BackgroundPatients with Fabry disease (FD) and amenable mutations can be treated with the chaperone migalastat to restore endogenous α-galactosidase A (AGAL) activity. However, certain amenable mutations do not respond biochemically in vivo as expected. Here, we aimed to establish a patient-specific and mutation-specific cell model to evaluate the amenability to chaperone therapy in FD.MethodsSince current tests to determine amenability are limited to heterologous mutation expression in HEK293T cells with endogenous AGAL activity, we generated CRISPR/Cas9-mediated AGAL-deficient HEK293T cells as a basis for mutant overexpression. Furthermore, primary urinary cells from patients were isolated and immortalised as a patient-specific cell model system to evaluate the amenability to chaperone therapy.ResultsUnder treatment (>13 months), carriers of p.N215S (n=6) showed a significant reduction of plasma lyso-Gb3 (p<0.05). Lyso-Gb3 levels in carriers of p.L294S increased (p<0.05) and two patients developed severe albuminuria. Both missense mutations were amenable in wild-type HEK293T cells (p<0.05), but presented different responses in CRISPR/Cas9-mediated AGAL knockouts and immortalised urinary cells. Chaperone incubation resulted in increased AGAL activity (p<0.0001) and intracellular globotriaosylceramide (Gb3) reduction (p<0.05) in immortalised p.N215S cells but not in p.L294S and IVS2+1 G>A cells.ConclusionWe conclude that repeated AGAL activity measurements in patients’ white blood cells are mandatory to assess the in vivo amenability to migalastat. Plasma lyso-Gb3 might be an appropriate tool to measure the biochemical response to migalastat. Patients with low AGAL activities and increasing lyso-Gb3 levels despite in vitro amenability might not benefit sufficiently from chaperone treatment.

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Although several reports suggest an increased thromboembolic event rate, especially regarding strokes and TIAs at early age in patients with Fabry disease (FD), the risk for patients with FD to experience these events, the clinical relevance of additional risk factors including the concurrence of factor V Leiden (FVL), and the benefit of enzyme replacement therapy (ERT) regarding these events remain unclear.

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In the present study, the [Β.sub.3]-adrenoceptor gene was screened for nucleotide variations. Three genetic variants were found (numbered according to the published sequence [1]). At nucleotide position 827, the previously [...]

The CXC chemokine receptor 3 (CXCR3) has been linked to autoimmune and inflammatory disease, allograft rejection, and ischemic nephropathy. CXCR3 is expressed on endothelial and smooth muscle cells. Although a recent study posited that antagonizing of CXCR3 function may reduce atherosclerosis, the role of CXCR3 in controlling physiological vascular functions remains unclear. This study demonstrates that disruption of CXCR3 leads to elevated mean arterial pressures in anesthetized and conscious mice, respectively. Stimulation of isolated resistance vessels with various vasoconstrictors showed increased contractibility in CXCR3−/− mice in response to angiotensin II (ANG II) and a decreased vasodilatation in response to acetylcholine (ACh). The increased contractibility was related to higher ANG II type 1 receptor (AT1R) expression, whereas the decreased vasodilatation was related to lower M3-ACh receptor expression in the mesenteric arteries of CXCR3−/− mice compared with wild-type mice. The vasodilatatory response to ACh could be antagonized by the nonselective ACh receptor antagonist atropine and the selective M3 receptor antagonist 4-DAMP, but not by M1, M2, and M4 receptor antagonists. Additionally, EMSA studies revealed that transcription factors SP-1 and EGR-1 interact as a complex with the murine AT1R promoter region. Furthermore, we could show increased expression of SP-1 in CXCR3−/− mice indicating an imbalanced SP-1 and EGR-1 complex formation which causes increased AT1R expression and hypertension. The data indicate that CXCR3 receptor is important in vascular contractility and hypertension, possibly through upregulated AT1R expression.

Previous studies found significant association of hypertension and hypertension-related phenotypes with genetic variation in SAH (Spontaneously hypertensive rat-clone A–Hypertension-associated). We sought independent confirmation of these findings in the European Project On Genes in Hypertension.

Identification and functional characterization of variants in the neutrophil elastase (ELA2) gene in cardiovascular disease.

The SAH gene locus has recently been proposed to be involved in obesity-related hypertension in Japanese individuals.

The regulator of G-protein signalling-2 (RGS2) is a key factor in adipogenesis. We hypothesized that the metabolic syndrome, of which obesity is an important component, might be related to genetic variation in RGS2.

Vascular endothelial cells control vascular smooth muscle tone via the release of nitric oxide. Following adverse circulatory conditions, namely trauma and hemorrhage, endothelial cell dysfunction occurs, leading to a decrease in the release of endothelium-derived nitric oxide, which contributes to further alterations in tissue perfusion and organ function.

Hypertension is a chronic age-related disorder, affecting nearly 20 of all adult Europeans. This disease entails debilitating cardiovascular complications and is the leading cause for drug prescriptions in Europeans older then 50 years. Intensive research over the past two decades failed so far to identify common genetic polymorphisms with major impact on blood pressure or associated cardiovascular phenotypes, suggesting that multiple genes each with a minor impact, along with gene-gene and gene-environment interactions play a role. The European Project on Genes in Hypertension (EPOGH) is a large-scale family-based study, in which participants from 7 different populations were phenotyped and genotyped according to standardised procedures. This review article summarizes the initial 5-year findings and puts these observations into perspective against other published studies. EPOGH demonstrated that phenotype-genotype relations strongly depend on host factors, such as gender and lifestyle, in particular salt intake as reflected by the 24-hour urinary excretion of sodium. EPOGH therefore highlights the concept that phenotype-genotype relations can only be studied within a defined ecogenetic context.

Carotid intima-media thickness (IMT) reflects generalized atherosclerosis and is predictive of future vascular events. Evidence exists that carotid IMT is heritable, and genetic studies can provide clues in the pathogenesis of atherosclerosis.

Hypertension is a chronic age-related disorder, affecting nearly 20% of all adult Europeans. This disease entails debilitating cardiovascular complications and is the leading cause for drug prescriptions in Europeans older than 50 years. Intensive research over the past two decades has so far failed to identify common genetic polymorphisms with a major impact on blood pressure or associated cardiovascular phenotypes, suggesting that multiple genes each with a minor impact, along with gene–gene and gene–environment interactions, play a role. The European Project on Genes in Hypertension (EPOGH) is a large-scale, family-based study in which participants from seven different populations were phenotyped and genotyped according to standardized procedures. This review article summarizes the initial 5-year findings and puts these observations into perspective against other published studies. The EPOGH demonstrated that phenotype–genotype relations strongly depend on host factors such as gender and lifestyle, in particular salt intake as reflected by the 24-h urinary excretion of sodium. The EPOGH therefore highlights the concept that phenotype–genotype relations can only be studied within a defined ecogenetic context.

The peroxisome proliferator-activated receptor γ (PPARγ) Pro12Ala polymorphism affects plasma lipids, but to what extent alcohol intake interferes with this association remains unknown. We randomly recruited 251 nuclear families (433 parents and 493 offspring) in the framework of the European Project on Genes in Hypertension study and genotyped 926 participants in whom all serum lipid variables and information on alcohol consumption were available for PPARγ2 Pro12Ala. Genotype-phenotype relations were assessed using generalized estimating equations (GEE) and a quantitative transmission disequilibrium test (QTDT). The Ala12 allele was more frequent in Novosibirsk (0.17) than in Cracow (0.12) and Mirano (0.11) (P < 0.01). Using GEE (P = 0.03) or QTDT (P = 0.007), Italian offspring carrying the Ala12 allele had higher serum HDL cholesterol than noncarriers. HDL cholesterol levels were on average 0.086 mmol/l (P = 0.001) higher in drinkers than in nondrinkers. Compared with Pro12 homozygotes, Ala12 allele carriers consuming alcohol had higher serum total and HDL cholesterol, with the opposite trend occurring in nondrinkers. This genotype-alcohol interaction was independent of the type of alcoholic beverage and more pronounced in moderate than in heavy drinkers. We conclude that alcohol intake modulates the relation between the PPARγ2 Pro12Ala and HDL cholesterol level and that, therefore, the Pro12Ala polymorphism, pending confirmation of our findings, might affect cardiovascular prognosis.

The polymorphic angiotensinogen (AGT) gene is one of the most promising candidates for blood pressure (BP) regulation and essential hypertension.

We hypothesized that the HMG-CoA reductase inhibitor fluvastatin, does not only improve endothelium-dependent vasorelaxation, but that it also increases vascular smooth muscle reactivity in hyperlipoproteinemia. New Zealand White (NZW) rabbits aged 37 weeks (control), Watanabe Heritable Hyperlipidemic rabbits (WHHL) aged 37 weeks, and WHHL aged 35 weeks with fluvastatin treatment of 17 weeks (10 mg/kg/d) were examined. Aortas were isolated for isometric tension recording. Both endothelium-dependent and independent relaxation were impaired in WHHL. Fluvastatin significantly restored impaired endothelium-independent relaxation (WHHL 57 ± 12 versus WHHL fluvastatin 150 ± 22; P< 0.05) and in tendency endothelium-dependent relaxation (WHHL 26 ± 5 versus WHHL fluvastatin 83 ± 29; (P0.07)). In parallel, fluvastatin restored nitrite plasma level in hyperlipoproteinemic animals (WHHL 480 (13–3821) versus WHHL fluvastatin 808 (467–1595) nmol; P< 0.05). Thus, chronic treatment with fluvastatin not only improves endothelial but also vascular smooth muscle function in hyperlipoproteinemia, which may contribute to the beneficial clinical effects of statins.

Human endothelin-converting enzyme (ECE)-1, the key enzyme in endothelin biosynthesis, shows broad cell and tissue expression within the cardiovascular system. Expression of ECE-1c, which represents the major ECE-1 isoform, is directed by an alternative promoter, but the mechanisms of ECE-1c promoter regulation are largely unknown. As ECE-1c transcription is initiated from several start sites, we hypothesized that the ECE-1c promoter functions as a housekeeping promoter.

To evaluate the efficiency of 4 radiofrequency (RF) systems by assessing the amount of delivered energy for each thermal induced lesion after perfusion mediated RF ablation and to compare the influence of perfusion mediation types on the energy efficiency.

The 825Tallele of the G-protein β3-subunit gene is associated with increased intracellular signalling and adipogenesis in experimental studies. We studied the C825Tpolymorphism in relation to blood pressure, obesity and intermediate phenotypes in a Caucasian population.

In a Caucasian population, the prevalence and incidence of hypertension, renal function and large artery stiffness were significantly correlated with polymorphisms in the genes encoding the angiotensin-converting enzyme (ACE I/D), aldosterone synthase (−C344T) and the cytoskeleton protein α-adducin (Gly460Trp).

The β2-adrenoceptor (ADRB2) plays a pivotal role in signalling in relation to hypertension and obesity. Polymorphisms of the ADRB2gene have been shown to be potentially related to essential hypertension and other non-cardiovascular disease phenotypes. We investigated whether genetic variation of the ADRB2gene might be related to essential hypertension or myocardial infarction (MI).

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, α-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 μmol/L for serum creatinine; 84 and 88 mL/min/1.73 m2for 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 m2) was nearly 11%. In single-gene analyses with adjustment for significant covariables, the risk for mild renal dysfunction was positively associated with the ACE Dallele. However, multiple-gene analyses showed that these associations were restricted to carriers of the mutated α-adducin Trpallele (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 μmol/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 Dsubjects than ACE IIhomozygotes, respectively. The aldosterone synthase Tallele did not strengthen genetic associations with the ACE Dallele considered alone or in combination with the α-adducin Trpallele. Thus, in the present cross-sectional analysis, renal function was slightly but consistently impaired when both the ACE Dand α-adducin Trpalleles 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 Dand α-adducin Trpalleles. © 2001 by the National Kidney Foundation, Inc.

The genes encoding angiotensin converting enzyme (ACE, I/D), α-adducin (ADD, Gly460Trp) and aldosterone synthase (AS, −344C/T) share the potential of influencing blood pressure (BP) via sodium homeostasis. However, most studies in humans focused on single-gene effects and disregarded epistasis, the suppression or potentiation of a gene by other non-allelic genes.

In genome-wide studies, the intercellular adhesion molecule-1 (ICAM-1) locus has been associated with cardiovascular and inflammatory bowel diseases. To determine the functional relevance of five missense ICAM-1 variants (G241R; I316V; P352L; K469E; R478W), we generated wild-type and variant proteins M2(241R); M3(469E); M4(352L); M5(478W); M6(316V); M7(352L469E) and transiently transfected CV1 cells. Reverse transcription PCR, western blot, and ELISA did not reveal any differences in mRNA and protein expression levels for any construct. Conversely, in pulse-chase experiments, compared with wild-type (90–120 min), M3 and M5 possessed a prolonged half-life of ∼150 min, whereas M2, M4, and M7 displayed a decreased half-life of ∼60–75 min, implying differences in protein degradation. Our results do not indicate a major impact of missense variants on ICAM-1 biological function, even if G241R and K469E were functional in pulse-chase experiments. Whether these differences in protein stability exert measurable functional consequences needs to be elucidated further.

Previous literature on price discovery in commodity markets is mainly focused on the question of whether the spot or the futures market dominates the price discovery process. Little attention, however, has been paid to the question of how the price discovery process is affected by futures speculation. Using different measures for speculation and hedging and a new price discovery metric, the present study analyzes this relationship for various agricultural commodities. On the whole, the results suggest that speculative activity reduces the level of noise in the futures markets under analysis, while increasing their relative contribution to the price discovery process.

Endothelin-1 is a potent vasoconstrictor that has also mitogenic properties, stimulating the synthesis and secretion of several vasoactive molecules. There is much evidence to suggest that endothelin-1 might be involved in the pathogenesis of hypertension, atherosclerosis, and ischemic heart disease. Endothelin-1 exerts its effects through at least two receptors, ETA and ETB, which are encoded by different genes and have separate tissue distributions and biologic properties. The objective of this study was to identify polymorphisms of the ETA and ETB receptor genes and to study their association with myocardial infarction (MI) and blood pressure. The coding regions and 1.3 kb upstream of the ETA and ETB receptor genes were explored by polymerase chain reaction/single strand conformation polymorphism. Six polymorphisms were found in the ETA receptor gene and three in the ETB receptor gene. Most of these polymorphisms were frequent. Associations between the detected polymorphisms, blood pressure, and MI were examined in the ECTIM study, a multicenter study comparing 652 patients having survived an MI and 773 controls from Belfast (Northern Ireland) and France. Alleles at the different polymorphic sites were similarly distributed in patients with MI and controls. Allele frequencies were similar in both countries, except for the ETA/-231 G allele, which appeared more frequently in France than in Belfast (P .01). The mean systolic and diastolic blood pressure levels did not significantly differ between genotypes. However, a C/T substitution located in the nontranslated part of exon 8 of the ETA receptor gene (ETA/EX8nt1363) was associated with pulse pressure (P < .005). These results do not support an involvement of the endothelin receptor genes in a predisposition to MI or the determination of blood pressure levels, but suggest that a polymorphism of the ETA receptor gene might influence the pulse pressure. This result will have to be confirmed in other studies. Am J Hypertens 1999;12:304310 © 1999 American Journal of Hypertension, Ltd.